@article {pmid41409674,
year = {2025},
author = {Sai, I and Grill, JD and Younes, K and Winer, JR and Cody, KA and Sperling, R and Mormino, EC and Young, CB},
title = {Cognitive screening biases in a secondary prevention Alzheimer's disease clinical trial.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.11.28.25341235},
pmid = {41409674},
abstract = {INTRODUCTION: Alzheimer's disease (AD) prevention trials have multiple screening steps to identify cognitively unimpaired individuals with AD biomarker evidence. Cognitive/functional screening tests may be biased in underrepresented groups, thereby impacting trial eligibility.

METHODS: 6669 participants screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were grouped by ethnoracial background and testing language. Ethnoracial/language differences in ineligibility reason, cognitive/functional test performance, and amyloid positivity rates were examined.

RESULTS: Ethnoracial minorities were least likely to meet eligibility criteria. Patterns of incorrect Mini-Mental State Examination items and impaired Clinical Dementia Rating functional domains differed between groups excluded for impaired cognition/function, suggesting test biases. The Free and Cued Selective Reminding Test yielded more similar exclusion rates across groups than Logical Memory. Cognitive/functional screening biases may impact subsequent biomarker screening as amyloid positivity rates were lowest in ethnoracial minorities.

DISCUSSION: Biases in cognitive/functional screening tests may disproportionately exclude ethnoracial minorities in AD prevention trials.},
}

@article {pmid41408986,
year = {2025},
author = {Liu, C and Ene, J and Lu, W and Syed, F and Sun, L and Raulin, AC and Ren, Y and Wang, X and Kanekiyo, T and Li, Y},
title = {Immuno-Regulation of Brain Region-Specific Organoids Containing Isogenic Microglia-Like Cells.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e03579},
doi = {10.1002/adhm.202503579},
pmid = {41408986},
issn = {2192-2659},
support = {2017869//NSF/ ; R01NS125016//Foundation for the National Institutes of Health/ ; R21EB033495//Foundation for the National Institutes of Health/ ; },
abstract = {Most brain organoids derived from human induced pluripotent stem cells (iPSCs) lack microglia and thus immune function. Microglia-like cells (MGCs) can be differentiated from iPSCs, while the characteristics of isogenic MGC-containing brain organoids in modeling neurodegeneration and cell-cell communications have not been well investigated. In this study, iPSC-derived MGCs are co-cultured with isogenic forebrain cortical organoids (iFCo), which are stimulated with extracellular vesicles (EVs) of brain organoids differentiated from Alzheimer's disease (AD) patient-derived iPSCs (APOE ε4/ε4 and presenilin 1). The AD EV-stimulated co-culture organoids are treated with EVs from healthy MGCs or co-culture. Differential responses of the co-cultured organoids and the MGCs to AD EVs are demonstrated. The co-cultured organoids mitigated pro-inflammatory gene expressions. EVs from healthy MGCs or co-culture reduced the expression of IL-12β, iNOS, TREM2, and CASS4, which are associated with neural inflammation and degeneration, as well as showed regulation on genes involved in microglial activation and carbon metabolism. AD EV cargo analysis by proteomics and microRNA-sequencing revealed APOE and APP proteins and microRNAs regulated pathways such as mitophagy. This study paves the way for understanding the role of microglia and brain organoids in modeling neural degeneration and the development of EV-based cell-free therapeutics for AD treatment.},
}

@article {pmid41408378,
year = {2025},
author = {Neuharth, JI and Hernandez, KS and Bernholtz, J and Edwards, H and Stewart, A},
title = {Consideration of sex as a biological variable over the history of the 5xFAD Alzheimer's Disease mouse model.},
journal = {Biology of sex differences},
volume = {16},
number = {1},
pages = {105},
pmid = {41408378},
issn = {2042-6410},
support = {NIH T32NS007421/NH/NIH HHS/United States ; Lulu Merle Johnson Recruitment Fellowship//University of Iowa/ ; },
mesh = {Animals ; *Alzheimer Disease ; Disease Models, Animal ; Male ; Female ; Mice ; Mice, Transgenic ; *Sex Characteristics ; },
abstract = {BACKGROUND: Women are nearly twice as likely to be diagnosed with Alzheimer's Disease (AD) over their lifetime. However, historically, preclinical studies utilizing AD rodent models to define new therapeutic targets in AD treatment have neglected to consider the confounding influence of subject sex leading to a lack of mechanistic insight into the biological underpinnings of sex bias in AD.

METHODS: Here, we tracked choice of subject sex over the twenty-year history of the 5xFAD mouse, one of the most frequently cited pre-clinical AD models. We analyzed 1,330 primary research articles indexed on PubMed and recorded information provided regarding subject sex and/or as a rationale for not including datasets separated by sex, if noted. Trends were then plotted as a function of time ending in December 2024.

RESULTS: In the last 15 years, the number of published manuscripts on the 5xFAD model omitting information on subject sex has progressively declined. However, the proportion of studies utilizing either males only (29%) or combining data from both sexes (24%) far surpasses studies acknowledging sex as a biological variable (SABV) (< 12%) with no significant changes noted over time. On average, the ratio of male only: female only studies of 5xFAD mice hovered around 2:1. The most frequently cited reason for omitting sex-based analyses was either a lack of sex differences found (29%), accelerated development of plaque burden in 5xFAD females (17%), or the possibility of within- or between-sex variability (15%). Mention of SABV has steadily increased in studies utilizing 5xFAD mice peaking at ~ 30% of manuscripts published in 2024. However, two key confounds in the 5xFAD model, including the potential impact of an estrogen response element (ERE) and parental imprinting in the Thy1 promoter driving transgene expression, have been largely ignored.

CONCLUSIONS: The 5xFAD model represents a compelling example of how neglecting to recognize the impact of biological sex on neural function can compromise study design and data interpretation. Given sex-dependent Thy1 promoter regulation may skew phenotypic outcomes, investigators should judiciously interpret sex differences observed in any AD mouse utilizing the Thy1 promoter to drive transgene expression.},
}

Animals
*Alzheimer Disease
Disease Models, Animal
Male
Female
Mice
Mice, Transgenic
*Sex Characteristics

@article {pmid41408021,
year = {2025},
author = {Kaur, K and Kulkarni, YA and Wairkar, S},
title = {Improved Oral Bioavailability and Brain Distribution of Hesperidin via Cochleate Formulation: Statistical Optimization and Pharmacokinetic Study.},
journal = {AAPS PharmSciTech},
volume = {27},
number = {1},
pages = {59},
pmid = {41408021},
issn = {1530-9932},
mesh = {*Hesperidin/pharmacokinetics/administration & dosage/chemistry ; Animals ; Biological Availability ; Rats, Wistar ; Administration, Oral ; Liposomes/chemistry ; Rats ; *Brain/metabolism ; Male ; Particle Size ; Chemistry, Pharmaceutical/methods ; Solubility ; Tissue Distribution ; Drug Liberation ; },
abstract = {Hesperidin, a flavanone, exhibits antioxidant, anti-inflammatory, and anti-amyloidogenic properties, making it a promising candidate for the treatment of Alzheimer's disease. The hesperidin possesses poor solubility, and its oral bioavailability is < 20%. Therefore, hesperidin cochleates (HC) were prepared using the trapping method of calcium ions into preformed liposomes to improve oral bioavailability. The HC formulation was statistically optimized by applying a 3-level factorial design. Optimum cochleates were observed, with an average particle size of 398.9 nm, a zeta potential of -39.1 mV, and an entrapment efficiency of 92.2%, respectively. The in vitro release of hesperidin from cochleates (Batch 15) was 97% in phosphate buffer at pH 7.4 after 24 h. The HC formulation exhibited a 1% release at a gastric pH of 1.2, indicating its stability in the stomach, allowing the formulation to reach the absorption site. In Wistar rats, a comparative pharmacokinetic study was conducted between hesperidin liposomes and HC. Hesperidin concentration was 2.21-fold higher in plasma and 1.2-fold higher in the brain after cochleates administration than in the liposomal formulation and more than 25-fold greater than plain API. Thus, cochleates may be superior oral carriers for hesperidin, improving its oral bioavailability for the treatment of Alzheimer's disease.},
}

*Hesperidin/pharmacokinetics/administration & dosage/chemistry
Animals
Biological Availability
Rats, Wistar
Administration, Oral
Liposomes/chemistry
Rats
*Brain/metabolism
Male
Particle Size
Chemistry, Pharmaceutical/methods
Solubility
Tissue Distribution
Drug Liberation

@article {pmid41407043,
year = {2025},
author = {Fan, B and Liang, Y and Zhi, T and Wu, L and Wu, Y and Yang, Y and Xie, Z and Wu, X},
title = {GPR55 deficiency exacerbates cognitive impairments and Alzheimer's disease-like pathology in mice.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106105},
doi = {10.1016/j.neuint.2025.106105},
pmid = {41407043},
issn = {1872-9754},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, characterized by progressive cognitive decline and neuronal damage. Although studies have indicated a link between G-protein coupled receptor 55 (GPR55) and AD-related cognitive impairment, the underlying mechanisms remain unclear. Here, we aim to further investigate the role of GPR55 in the pathogenesis of AD.

METHODS: We used viral vectors to knock down GPR55 expression in the hippocampus of normal mice. We also generated GPR55 knockout in AD mice by crossing GPR55[-/-] mice with APP/PS1 transgenic mice (APP/PS1; GPR55[-/-]). Behavioral tests were conducted to assess spatial memory deficits in 9-month-old APP/PS1; GPR55[-/-] mice. We also assessed the amyloid β (Aβ) deposition, glial cell activation, and synaptic protein expression in the hippocampus. In addition, we used AAV9 viruses to overexpress GPR55 in the hippocampus of APP/PS1; GPR55[-/-] mice to further observe its effect on cognitive function.

RESULTS: Knockdown of GPR55 in the hippocampus induces AD-like pathology, cognitive dysfunction, neuroinflammation, and synaptic plasticity damage in normal mice. This was evidenced by increased hippocampal levels of Aβ and p-Tau, enhanced glial cell activation accompanied by upregulation of proinflammatory cytokines, and aggravated synaptic plasticity damage in the normal mice. Furthermore, knockdown of GPR55 induced the reduction of P-AKT1/2/3/AKT1/2/3 and P-GSK3β/GSK3β, while increasing the expression of P-ERK1/2/ERK1/2 in the hippocampus of normal mice. In addition, GPR55 deficiency exacerbated AD-like pathology and spatial learning and memory deficits in APP/PS1 mice. Conversely, AAV9-mediated overexpression of GPR55 rescued spatial memory impairments in APP/PS1; GPR55[-/-] mice.

CONCLUSIONS: These findings underscore the critical role of GPR55 in AD progression and highlight its potential as a therapeutic target for AD treatment.},
}

@article {pmid41406951,
year = {2025},
author = {Fang, S and Cui, F and Drucker, DJ},
title = {Glucagon-like peptide-1 medicines in neurological and psychiatric disorders.},
journal = {Cell reports. Medicine},
volume = {6},
number = {12},
pages = {102511},
doi = {10.1016/j.xcrm.2025.102511},
pmid = {41406951},
issn = {2666-3791},
mesh = {Humans ; *Glucagon-Like Peptide 1/therapeutic use/metabolism ; *Mental Disorders/drug therapy ; *Nervous System Diseases/drug therapy ; Diabetes Mellitus, Type 2/drug therapy ; },
abstract = {Glucagon-like peptide-1 (GLP-1) medicines are used for the treatment of type 2 diabetes (T2D) and obesity and reduce rates of cardiovascular disease, including stroke, in people with T2D. Substantial evidence from real-world data and clinical trials highlights the therapeutic potential of GLP-1 medicines for the treatment of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Similarly, there is growing evidence for the potential utility of using GLP-1 medicines to reduce rates of smoking, or use of alcohol, tobacco, cannabis, or cocaine in individuals with substance use disorders. More limited clinical data suggest utility for GLP-1 medicines in patients with migraine or intracranial hypertension. The available data suggest that the use of GLP-1 medicines exhibits an acceptable safety profile in most individuals with neuropsychiatric disorders. Here, we review recent clinical evidence and ongoing trials exploring the efficacy and safety of GLP-1 medicines across a broad range of neurological conditions.},
}

Humans
*Glucagon-Like Peptide 1/therapeutic use/metabolism
*Mental Disorders/drug therapy
*Nervous System Diseases/drug therapy
Diabetes Mellitus, Type 2/drug therapy

@article {pmid41406583,
year = {2025},
author = {Yıldızbaş, A and Taslimi, P and Tüzün, B and Sadeghian, N and Kurt, R and İstek, A},
title = {Chemical composition and bioactivity of Sideritis taurica Stephan ex Wild. (Lamiaceae) leaves: GC/MS analysis, antioxidant and enzyme inhibition activities, and in silico studies.},
journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences},
volume = {1270},
number = {},
pages = {124894},
doi = {10.1016/j.jchromb.2025.124894},
pmid = {41406583},
issn = {1873-376X},
abstract = {Since ancient times, Sideritis taurica and other Sideritis species have been used in traditional medicine in Türkiye and beyond for treating a variety of ailments, including coughs, sore throats, gastrointestinal, respiratory, and urogenital disorders, as well as wounds, colds, and flu, and are believed to possess numerous therapeutic properties such as antispasmodic, analgesic, antibacterial, anti-inflammatory, and antioxidant effects. This study aimed to evaluate the enzyme inhibition and antioxidant activities of various extracts from S. taurica leaves collected from Kurucaşile, Bartın, Türkiye. The extracts were prepared using ethanol, methanol, and hot/cold water extraction methods from leaves that were dried at room temperature and stored in a freezer. Enzyme inhibition activities were assessed against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-glucosidase, and α-amylase, with IC50 values calculated. Antioxidant activities were measured using DPPH, ABTS, and CUPRAC assays. Furthermore, ADME/T (Absorption, Distribution, Metabolism, Excretion, and Toxicity) and molecular docking calculations were performed on the phytochemical components of S. taurica to investigate their effects and interactions with human metabolism. These calculations were performed on a number of proteins, including alpha-amylase protein (PDB ID: 1HNY), AChE protein (PDB ID: 4M0E), and BChE protein (PDB ID: 5NN0). The purpose of these calculations was to investigate the interaction between these substances and human metabolism. The results indicated that the ethanol and methanol extracts exhibited the highest inhibition on AChE and BChE (IC50 values of 73.99 μg/mL and 5.04 μg/mL, respectively). The methanol extracts also demonstrated potent inhibition against α-glucosidase (IC50 value of 25.81 μg/mL) and α-amylase (IC50 value of 70.42 μg/mL). Regarding antioxidant activity, the methanol extracts showed the highest radical scavenging activity in the DPPH (87.88 %) and ABTS (99.97 %) tests. Additionally, the methanol extracts stored in the freezer exhibited the best-reducing power in the CUPRAC assay (2.436 ± 0.1669). These findings underscore the potential of S. taurica as a source of natural antioxidants and enzyme inhibitors, suggesting its applicability in the treatment of neurodegenerative diseases such as Alzheimer's disease. In conclusion, extracts obtained from S. taurica leaves, particularly those derived from room temperature-dried leaves, demonstrate significant enzyme inhibition and antioxidant properties. Also, the findings support the consideration of S. taurica as a natural therapeutic source for neurodegenerative diseases and emphasize for further investigation into its active components and health benefits.},
}

@article {pmid41405876,
year = {2025},
author = {},
title = {Valacyclovir Treatment of Early Symptomatic Alzheimer Disease: Research Summary.},
journal = {JAMA},
volume = {},
number = {},
pages = {e2522830},
doi = {10.1001/jama.2025.22830},
pmid = {41405876},
issn = {1538-3598},
}

@article {pmid41405855,
year = {2025},
author = {Devanand, DP and Wisniewski, T and Razlighi, Q and Qian, M and Wei, R and Andrews, HF and Acosta, EP and Bell, KL and Pelton, GH and Deliyannides, D and Perrin, AC and Caccappolo, E and Gershon, AA and Prasad, KM and Kreisl, WC and Mintz, A and Huey, ED},
title = {Valacyclovir Treatment of Early Symptomatic Alzheimer Disease: The VALAD Randomized Clinical Trial.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2025.21738},
pmid = {41405855},
issn = {1538-3598},
abstract = {IMPORTANCE: Neuroscientific, epidemiological, and electronic health record studies implicate herpes simplex virus (HSV) as potentially etiological for Alzheimer disease (AD).

OBJECTIVE: To compare the efficacy and adverse effects of valacyclovir vs placebo in participants with early symptomatic AD and HSV seropositivity (HSV-1 or HSV-2).

This randomized clinical trial included adults with a clinical diagnosis of probable AD or a clinical diagnosis of mild cognitive impairment with positive biomarkers for AD, a positive serum antibody test (IgG or IgM) for HSV-1 or HSV-2, and a Mini-Mental State Examination score of 18 to 28. The trial was conducted at 3 US outpatient clinics specializing in memory disorders. Recruitment occurred from January 2018 to May 2022; the last follow-up occurred in September 2024.

INTERVENTION: Either 4 g/d of valacyclovir (n = 60) or matching placebo (n = 60).

MAIN OUTCOMES AND MEASURES: The primary outcome was least-squares mean (LSM) change at 78 weeks in the 11-item Alzheimer's Disease Assessment Scale Cognitive (ADAS-Cognitive) Subscale score (range, 0-70; higher scores indicate greater impairment). The secondary outcomes were LSM change in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Scale score; LSM change in the 18F-florbetapir amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR; higher scores indicate higher amyloid levels) for 6 brain regions (medial orbitofrontal, anterior cingulate, parietal lobe, posterior cingulate, temporal lobe, and precuneus); and LSM change in 18F-MK-6240 tau PET medial temporal SUVR (higher scores indicate higher tau levels) for 4 brain regions (amygdala, hippocampus, entorhinal, and parahippocampus). The frequency of adverse events was the safety outcome.

RESULTS: Of the 120 participants (mean age, 71.4 [SD, 8.6] years; 55% were female), 93 (77.5%) completed the trial. At 78 weeks, the LSM change in the 11-item ADAS-Cognitive Subscale score was 10.86 (95% CI, 8.80 to 12.91) in the valacyclovir group vs 6.92 (95% CI, 4.88 to 8.97) in the placebo group, indicating greater cognitive worsening with valacyclovir than placebo (between-group difference, 3.93 [95% CI, 1.03 to 6.83]; P = .01). The LSM change in the ADCS-ADL Scale score at 78 weeks was -13.78 (95% CI, -17.00 to -10.56) in the valacyclovir group vs -10.16 (95% CI, -13.37 to -6.96) in the placebo group (between-group difference, -3.62 [95% CI, -8.16 to 0.93]). At 78 weeks, the LSM change in the 18F-florbetapir amyloid PET SUVR was 0.03 (95% CI, -0.04 to 0.10) in the valacyclovir group vs 0.01 (95% CI, -0.06 to 0.08) in the placebo group (between-group difference, 0.02 [95% CI, -0.08 to 0.12]). The LSM change in the 18F-MK-6240 tau PET medial temporal SUVR at 78 weeks was 0.07 (95% CI, -0.06 to 0.19) in the valacyclovir group vs -0.04 (95% CI, -0.15 to 0.07) in the placebo group (between-group difference, 0.11 [95% CI, -0.06 to 0.28]). The most common adverse events were elevated serum creatinine level (5 participants [8.3%] in the valacyclovir group vs 2 participants [3.3%] in the placebo group) and COVID-19 infection (3 [5%] vs 2 [3.3%], respectively).

CONCLUSIONS AND RELEVANCE: Valacyclovir was not efficacious with cognitive worsening for the primary outcome and it is not recommended to treat individuals with early symptomatic AD and HSV seropositivity.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03282916.},
}

@article {pmid41405805,
year = {2025},
author = {Blair, HA},
title = {Sublingual Cyclobenzaprine: First Approval.},
journal = {Clinical drug investigation},
volume = {},
number = {},
pages = {},
pmid = {41405805},
issn = {1179-1918},
abstract = {TONMYA[™] is a sublingual eutectic formulation of cyclobenzaprine being developed by Tonix Pharmaceuticals for the treatment of various conditions, including fibromyalgia, post-traumatic stress disorder (PTSD), acute stress disorder, major depressive disorder, post-acute COVID-19 syndrome, alcohol use disorder, and agitation in Alzheimer's disease. The sublingual formulation was designed for rapid transmucosal absorption to produce diurnal variation in peak-to-trough drug concentrations, making it suitable for long-term bedtime use. On 15 August 2025, sublingual cyclobenzaprine was approved for the treatment of fibromyalgia in adults in the USA. This article summarizes the milestones in the development of sublingual cyclobenzaprine leading to this first approval for fibromyalgia.},
}

@article {pmid41404527,
year = {2025},
author = {Nestor, PJ and Pelekanos, M and Leinenga, G and Song, J and Lee, W and Richter-Stretton, G and McElligott, C and Fazlollahi, A and Mattingley, JB and Harris, A and Beale, H and Roberts, J and de Las Heras, R and Götz, J},
title = {A pilot safety and tolerability study of scanning ultrasound as a neuromodulation therapy in Alzheimer's disease.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf445},
pmid = {41404527},
issn = {2632-1297},
abstract = {Clearing amyloid-β pathology in Alzheimer's disease (AD) has been considered a prerequisite for restoring cognitive functions. Intriguingly, by application of a modality of scanning ultrasound (SUS) to mice that does not remove amyloid-β, we previously achieved significant cognitive improvements. This prompted us to explore SUS as a non-invasive brain stimulation strategy in an open-label safety trial in AD. We conducted a human pilot study in 12 participants with AD with the primary objective of determining feasibility, safety and tolerability. Exploratory secondary end-points were cognitive and behavioural measures, resting-state EEG and functional MRI. A portable device termed UltraThera[Pilot] was built under medical device standard guidelines, integrating a Brainsight image-guided neuronavigation system. A single-element 286-kHz transducer was programmed to deliver non-derated ultrasound doses of 2.6, 1.95 or 1.3 MPa. With four treatment sessions spaced fortnightly, four participants received 30 sonications per session (precuneus, ∼30 cm[3] brain tissue) and the remaining 8 received 100 sonications per session (bilateral precuneus and temporo-parietal association cortex, ∼100 cm[3]). Safety monitoring, EEG, MRI, cognitive and neuropsychiatric evaluations were performed. The treatment was fast, safe and well-tolerated at the 1.95 MPa dose. MRI showed no changes, whereas changes were observed in aperiodic EEG content. Cognitive performance did not change but statistically significant improvements in behavioural and psychological symptoms were found using the Neuropsychiatric Inventory test. In conclusion, this SUS safety trial met its primary and secondary end-points in biomarker-confirmed mild-to-moderate AD. It informs our future work in an upcoming efficacy trial in an AD population.},
}

@article {pmid41404461,
year = {2025},
author = {Li, W and Liu, X and Gao, C and Li, W and Liao, X},
title = {Network meta-analysis of the efficacy of pharmacological treatments for post-stroke cognitive impairment and vascular cognitive impairment.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1683496},
pmid = {41404461},
issn = {1664-2295},
abstract = {BACKGROUND: Based on recent reviews, vascular cognitive impairment (VCI) encompasses a spectrum of cognitive deficits caused by cerebrovascular disease and its risk factors, ranging from mild cognitive impairment to dementia, and often coexists with neurodegenerative conditions like Alzheimer's disease. VCI is categorized into four clinical-imaging subtypes, including post-stroke cognitive impairment (PSCI)-a common stroke complication and major VCI subtype. Current guidelines recommend cholinesterase inhibitors and NMDA receptor antagonists as first-line treatments for VCI, with expert consensus supporting donepezil and rivastigmine for PSCI. However, existing evidence primarily derives from placebo-controlled or head-to-head drug comparisons, lacking comprehensive evaluations of multiple cognitive enhancers. This study aims to systematically assess the efficacy and safety of cognitive-enhancing drugs in VCI, with a focused analysis on PSCI, to better inform clinical decision-making and improve patient outcomes.

METHODS: We systematically searched four databases using predefined search strategies. Eligible studies were selected based on predetermined criteria. The included studies were analyzed with StataSE 16.0, RevMan 5.3, and Grade software to compare the efficacy and safety of cognitive-enhancing drugs to identify the optimal treatment for VCI and PSCI.

RESULTS: Sixteen studies (5,599 participants) were included. In terms of cognitive outcomes, sailuotong was superior to placebo on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) (MD = -3.00, 95% CI: -4.50, -1.50) and ranked best (SUCRA 88.5%). Memantine was most effective on the Mini-Mental State Examination (MMSE) (MD = 1.23, 95% CI: 0.23-2.23; SUCRA 80.8%). For the secondary outcome, the MoCA assessment showed that Ginkgo biloba extract significantly improved Montreal Cognitive Assessment (MoCA) scores compared to placebo (MD = 1.29, 95% CI: 1.24, 1.35). Regarding safety, donepezil significantly increased the risk of overall adverse events compared to placebo (OR: 1.57; 95% CI: 1.19-2.06).

CONCLUSION: Our network meta-analysis suggests that memantine might have the best effect for PSCI, with sailuotong potentially serving as a secondary option. However, these estimates are based on a small randomized controlled trial and a sparse network. Therefore, the current evidence is limited, highlighting the need for more high-quality studies to robustly validate the therapeutic potential of these interventions for VCI and PSCI.

https://www.crd.york.ac.uk/PROSPERO/, identifier in PROSPERO (CRD420250627957).},
}

@article {pmid41404160,
year = {2025},
author = {Roche, S and Naran, N and Scholtz, J and Liu, KY and Reeves, S and Howard, R},
title = {Systematic review and meta-analysis of antipsychotic discontinuation in dementia.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70188},
pmid = {41404160},
issn = {2352-8737},
abstract = {INTRODUCTION: Antipsychotics are used to treat behavioral and psychological symptoms of dementia (BPSD). However, treatment is associated with adverse outcomes. A 2018 Cochrane review found low-quality evidence that discontinuation may have little effect on BPSD by primarily comparing the difference in number of study non-completers between treatment groups and did not report a pooled effect size for relapse risk. We performed a meta-analysis of the pooled risk ratio (RR) of relapse of symptoms following antipsychotic medication discontinuation in people with dementia. We hypothesized that trial design (enriched responder samples vs long-term user withdrawal), treatment duration, length of follow-up, withdrawal speed, and sex of participants would affect relapse risk.

METHODS: We systematically searched PsycINFO, EMBASE, PubMed, and ClinicalTrials.gov databases for studies published between January 2018 and June 2024. The eight papers identified in the 2018 Cochrane review were also included in the meta-analysis. The study was registered with PROSPERO (CRD42024570329).

RESULTS: A total of nine studies were included, providing 682 observations with 135 events. Relapse definitions included participant removal due to worsening behavior or starting regular prescription of antipsychotic/rescue medication. A random-effects model found a pooled RR of relapse of 1.52 (95% CI: 1.18 to 1.95, p = 0.005) with stopping antipsychotics. Meta-regressions showed no effect of trial type, withdrawal speed, length of follow-up, or participant sex on RR.

DISCUSSION: While it is important to prescribe cautiously and to reduce and withdraw prescriptions in those who are considered to no longer need antipsychotics, there is a subgroup of patients for whom continuing medication is important. It was particularly surprising that the relative risk of relapse was unaffected by trial design, with similar effect sizes in both trials aiming to reduce prescription and prove efficacy. Further research is needed to identify factors associated with successful antipsychotic withdrawal.

HIGHLIGHTS: An updated meta-analysis of trials of withdrawal of antipsychotics in dementia.Relative risk of symptom relapse increased when stopping antipsychotics.Relapse risk was not affected by trial design or prior length of treatment.Relapse risk was not affected by length of follow-up, withdrawal speed, or sex.},
}

@article {pmid41403906,
year = {2025},
author = {Duan, Y and Han, C and Zheng, H and Yu, J and Luo, M},
title = {Global, regional, and national burden of Alzheimer's disease and other dementias from 1990 to 2021: findings from the Global Burden of Disease Study 2021.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1678212},
pmid = {41403906},
issn = {1663-4365},
abstract = {BACKGROUND: As the global population continues to age, the growing number of elderly individuals has contributed to an increase in age-related conditions and illnesses, such as dementia, which places considerable financial and emotional pressure on both families and society. Alzheimer's disease (AD), the most prevalent form of dementia among the elderly, significantly impacts their quality of life and ability to perform daily activities independently. Over the past three decades, the age-standardized mortality rate has declined and life expectancy has steadily increased worldwide. However, this long-term progress was disrupted by the COVID-19 pandemic, which reversed some of the gains made in life expectancy and contributed to a global decline. The pandemic has notably affected global health, exacerbating the prevalence of Alzheimer's disease and other dementias (ADOD).

METHODS: In line with the analytical approach used in the Global Burden of Disease Study (GBD) 2021, we examined the counts and age-standardized rates (ASR) for the prevalence, incidence, mortality, and Disability-Adjusted Life Years (DALYs) associated with ADOD, categorized by region, country, sex, and age from 1990 to 2021. To assess temporal patterns over the study period, we calculated the estimated annual percentage changes (EAPCs).

RESULTS: From 1990 to 2021, both the number and age-standardized rates (ASR) of prevalence, incidence, mortality, and DALYs associated with ADOD showed a significant increase globally. Regionally, high-middle SDI regions had the highest ASPR at 766.2 per 100,000 (95% UI: 659.8, 879.6), with the most considerable rise, reflected in an EAPC of 0.21 (95% CI: 0.17, 0.25). In East Asia, the highest age-standardized incidence rate (ASIR) was reported, at 149.6 (95% UI: 129.6, 171.1) per 100,000 people, along with the greatest increase in ASIR, at 0.4 (95% UI: 0.33, 0.47) among the 21 GBD regions. On a national level, China experienced the greatest burden of ADOD, with the highest ASPR of 900.8 (95% UI: 770.9, 1043.2) and the highest ASIR of 151.5 (95% UI: 131.2, 173.3) per 100,000 people. The 80-84 age group exhibited the highest rates of prevalence, incidence, and DALYs, whereas the number of deaths in the 85-89 age group surpassed those in other age categories. Throughout all age groups, females experienced a higher burden of ADOD than males, regardless of the time or geographical location. The burden of ADOD reached its lowest point in 2019 but has increased steadily since then.

CONCLUSION: In summary, this study highlights the global epidemiological trends of ADOD from 1990 to 2021, including the impact of the COVID-19 pandemic on it. As the population ages, ADOD has emerged as a significant public health concern worldwide. Although some regions have made progress in managing the burden of ADOD, most regions and countries still face a heavy disease burden. More effective prevention and treatment strategies are needed to alleviate the impact of ADOD. In particular, greater focus should be placed on women and the elderly.},
}

@article {pmid41403678,
year = {2025},
author = {Sinan Tokalı, F and Şenol, H and Demir, Y and Uluçay, O and Ameen, M and Shafiq, Z},
title = {New Mannich-type arylidenerhodanines as potent inhibitors of AChE and BChE: synthesis, biological evaluation, cytotoxicity and molecular modeling.},
journal = {RSC advances},
volume = {15},
number = {58},
pages = {50186-50205},
pmid = {41403678},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with a gradual increase in severity. The underlying cause of the disease is the dysfunction of cholinergic neurotransmission affecting mainly the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Within the context of the present research, a new group of 3,5-disubstituted rhodanine derivatives containing tertiary amine groups has been prepared and their potency in the inhibition of AChE and BChE was assessed. Enzymatic assays demonstrated that compounds 6 and 11 exhibited exceptional inhibitory potency, with K i values of 13.61 nM and 12.70 nM against AChE, and 10.44 nM and 25.11 nM against BChE, respectively, surpassing the reference inhibitors tacrine (145.21 nM for AChE and 169.54 nM for BChE) and donepezil (67.41 nM for AChE and 62.44 nM for BChE). Cytotoxicity studies confirmed minimal toxicity in human umbilical vein endothelial cells (HUVEC) at concentrations several times higher than the effective inhibitory doses (IC50 = 79.13 µM for 6 and 69.14 µM for 11). The results from molecular docking and MM-GBSA calculations supported this presumption by foretelling strong binding affinities, where compound 11 was the one to show a free energy of -103.26 kcal mol[-1] for AChE and compound 6 -86.75 kcal mol[-1] for BChE. Moreover, the 250 ns molecular dynamics simulations gave a confirmation of the structural stability and the prolonged existence of the key interactions in the enzyme active sites during the entire time. The findings of this research emphasize compounds 6 and 11 as potential candidates for the creation of strong cholinesterase inhibitors for the treatment of Alzheimer's disease, thus encouraging additional studies.},
}

@article {pmid41403033,
year = {2025},
author = {Berthier, ML and Sosa-Welford, A and Orozco-Arroyave, JR and López-Barroso, D and Torres-Prioris, MJ and Dávila, G and García, AM},
title = {Speech and language outcome measures in clinical trials of Alzheimer's and Parkinson's diseases.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-20},
doi = {10.1080/14737175.2025.2600616},
pmid = {41403033},
issn = {1744-8360},
abstract = {INTRODUCTION: Alongside core diagnostic symptoms, Alzheimer's disease (AD) and Parkinson's disease (PD) involve early and pervasive speech-language impairments (SLI), often appearing in preclinical stages and capturing disease severity. However, speech language outcome measures are under-represented in clinical trials, missing out on critical clinical outcome assessments (COAs).

AREAS COVERED: The purpose of this review is to survey the findings from classical (analogical) and novel (digital) speech-language measures as pathways toward more precise diagnosis and response to treatment indices in interventional clinical trials. This narrative review covers two main areas; first, it examines the strengths and limitations of SL measures in traditional cognitive testing scales to identify adequate COAs for AD and PD. Second, it overviews findings on classical and digital COAs that hold great promise despite their widespread absence in clinical trials.

EXPERT OPINION: Incorporating strategic SL COAs in clinical trials may identify early, severity-sensitive deficits and enhance the clinical insights thus obtained. The modification of clinical trial designs will nevertheless be required to increase sensitivity to identify meaningful clinical outcomes.},
}

@article {pmid41402453,
year = {2025},
author = {Rasà, DM and Stanga, S and Santonicola, P and Mazzarella, N and Camera, A and Matino, I and Zampi, G and Boido, M and Di Schiavi, E and Vercelli, A},
title = {10H-phenothiazine exerts beneficial effects in spinal muscular atrophy in vitro and in vivo models.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-28547-9},
pmid = {41402453},
issn = {2045-2322},
support = {24401//AFM-Telethon/ ; 24401//AFM-Telethon/ ; GGP16203//Italian Telethon Foundation/ ; GGP16203//Italian Telethon Foundation/ ; Mission M4C2I1.3, PRR.AP015.118//National Recovery and Resilience Plan (NRRP)/ ; Department of Excellence//Ministry of University and Research (MUR)/ ; },
abstract = {Spinal Muscular Atrophy (SMA) is a neurodegenerative disorder affecting lower motor neurons (MNs) and leading to muscle atrophy, due to mutation of the SMN1 gene, which encodes SMN protein. Experimental studies also demonstrated the upper MN impairment. The available approved drugs for SMA increase the SMN protein production. Although effective, outcomes are dependent upon treatment timing and disease severity. Drug repositioning may represent a valid strategy to identify new treatments by repurposing FDA/EMA-approved drugs that, combined with the available ones, could delay neurodegeneration. To this aim, for the first time we used primary cortical neurons derived from the SMNΔ7 mice as defective in vitro disease model, to preliminary assess drug efficacy on neuronal survival and morphology. Under basal conditions, SMA cortical neurons showed significantly reduced vitality and altered morphology compared to WT neurons. All the parameters were rescued after treatment with known compounds (Valproic Acid, 4-aminopyridine and N-acetylcysteine), already tested in either preclinical or clinical context for SMA. We then investigated for the first time in SMA pathology the efficacy of 10H-phenothiazine (10H-PTZ), known to exert neuroprotection and to target altered mechanisms in Parkinson's and Alzheimer's disease. Its administration to SMA cortical neurons induced significant protective effects on both neuronal survival and morphology that were further confirmed in vivo, in a C. elegans SMA model. Overall, our results provide valuable insights, both in vitro and in vivo, into the potential of 10 H-PTZ repurposing for SMA, although additional functional studies will be required.},
}

@article {pmid41401902,
year = {2025},
author = {Li, HR and Shi, JZ and Zhang, MJ and Yun, LY and Zhou, YF and He, YY and Li, X and Du, GH and Pang, XB and Wang, MW and Xie, XM and Kou, JJ},
title = {Cftr Nominates a Novel Therapeutic Target for Alzheimer's Disease: Evidence from Integrative Omics and In Vitro Validation.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110808},
doi = {10.1016/j.neuropharm.2025.110808},
pmid = {41401902},
issn = {1873-7064},
abstract = {Alzheimer's disease (AD), among the most prevalent neurodegenerative disorders, poses substantial challenges for therapeutic development due to its complex pathophysiology, necessitating novel treatment strategies. This study applied an integrated transcriptomics and untargeted metabolomics approach to hippocampal tissues from wild-type and 3×Tg-AD mice to identify AD-associated molecular alterations and key pathways. KEGG pathway enrichment analysis of significantly differentially expressed genes and metabolites identified several core candidate genes, including C5ar1, Gabrg1, Ptger1, Tac1, Lpar2, Pnp2, Cftr, and Sstr3. PCR-based validation in both in vivo and in vitro models confirmed Cftr as the most promising candidate for further investigation. In Aβ25-35-induced cellular AD models, Cftr knockdown or pharmacological inhibition activated the NLRP3 inflammasome pathway, exacerbating neuroinflammation and oxidative stress, whereas enhancing Cftr activity attenuated these pathological processes. These results establish Cftr as a potential therapeutic target for AD and reveal that its modulation of NLRP3 inflammasome signaling represents a strategic avenue for mitigating neuroinflammation and oxidative stress, suggesting a promising direction for intervening in AD progression.},
}

@article {pmid41401892,
year = {2025},
author = {Jogeshwar, BK and Lu, S and Nephew, BC},
title = {Neuroanatomical-based machine learning prediction of Alzheimer's Disease across sex and age.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.12.030},
pmid = {41401892},
issn = {1873-7544},
abstract = {Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. In 2024 it affected approximately 1 in 9 people aged 65 and older in the U.S., 6.9 million individuals. Early detection and accurate AD diagnosis are crucial for improving patient outcomes. Magnetic resonance imaging (MRI) has emerged as a valuable tool for examining brain structure and identifying potential AD biomarkers. This study performs predictive analyses by employing machine learning techniques to identify key brain regions associated with AD using numerical data derived from anatomical MRI scans, going beyond standard statistical methods. Using the Random Forest Algorithm, we achieved 92.87 % accuracy in detecting AD from Mild Cognitive Impairment and Cognitive Normals. Subgroup analyses across nine sex- and age-based cohorts (69-76 years, 77-84 years, and unified 69-84 years) revealed the hippocampus, amygdala, and entorhinal cortex as con- sistent top-rank predictors. These regions showed distinct volume reductions across age and sex groups, reflecting distinct age- and sex-related neuroanatomical patterns. Younger males and females (aged 69-76) exhibited volume decreases in the right hippocampus, suggesting its importance in the early stages of AD. Older males (77-84) showed substantial volume decreases in the left inferior temporal cortex. The left middle temporal cortex showed decreased volume in females, suggesting a potential female-specific influence, while the right entorhinal cortex may have a male-specific impact. These age-specific sex differences could inform clinical research and treatment strategies, aiding in identifying neuroanatomical markers and therapeutic targets for future clinical interventions.},
}

@article {pmid41401852,
year = {2025},
author = {Huang, YW and Chan, HC and Khoo, JY and Chan, ML and Bender, D and Ponnusamy, VK and Belaidi, AA and Ke, LY},
title = {Assessing the critical role of ceramide in the pathogenesis of Alzheimer's disease and its clinical significance.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106104},
doi = {10.1016/j.neuint.2025.106104},
pmid = {41401852},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, and synaptic loss. Emerging evidence indicates that apolipoprotein E (APOE) polymorphism and dysregulated ceramide metabolism are critical links among these pathogenic processes. Ceramide accumulation in the brain contributes to Aβ generation, tau phosphorylation, and neuronal apoptosis. Elevated ceramide levels have been observed in plasma, cerebrospinal fluid, and peripheral organs such as the liver, reflecting systemic lipid dysregulation. Lipoproteins-particularly low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL)-transport ceramide across the blood-brain barrier, while apoE4 isoforms exacerbate this process by disrupting vascular integrity and lipid homeostasis. In addition, hepatic and gut-derived ceramides may influence neurodegeneration through the liver-gut-brain axis. Therapeutic interventions targeting ceramide synthesis (serine palmitoyltransferase inhibitors), production (neutral sphingomyelinase inhibitors), and the ceramide/sphingosine-1-phosphate (S1P) balance show potential in preclinical models for reducing Aβ pathology, tau aggregation, and neuroinflammation. These findings position ceramide metabolism as a critical mediator of AD pathogenesis and a promising target for diagnosis and treatment. Modulating ceramide and S1P signaling could complement current amyloid- and tau-directed therapies, offering new opportunities for disease modification and early intervention.},
}

@article {pmid41400820,
year = {2025},
author = {Al-Mayahi, S and Andersson, ML and Mo, M and Garcia-Ptacek, S and Xu, H and Wikström, E and Eriksdotter, M},
title = {Increased mortality in dementia patients using inhaled anticholinergics: A nationwide register study from the Swedish registry on dementia/cognitive disorders, SveDem.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251406309},
doi = {10.1177/13872877251406309},
pmid = {41400820},
issn = {1875-8908},
abstract = {BackgroundPatients with chronic obstructive pulmonary disease (COPD) face increased risks of cognitive impairment and mortality compared with the general population. Inhaled anticholinergics (LAMA/SAMA) are central in COPD treatment. The link between COPD and dementia is well studied, while effects of COPD medications on survival in dementia patients, have received limited attention.ObjectiveDescribe dementia patients using LAMA/SAMA in the Swedish Dementia Registry (SveDem) and compare survival between users (exposed) and non-users (unexposed).MethodsThis register-based study used data from SveDem and the Swedish Prescribed Drug Register to identify dementia patients using inhaled anticholinergics. All patients diagnosed with dementia between 2008-01-01 and 2017-12-31 were included. Exposed patients had at least one LAMA/SAMA dispensation per year in the two years prior the index date or more than one in the year before. Standardized-mortality-rates (SMR) were calculated, and survival analysed using Kaplan-Meier and Cox regression.ResultsA total of 74,018 dementia patients were included, of whom 3.5% had used inhaled anticholinergics. Alzheimer's disease was the most common dementia type. SMR was higher in exposed patients across all age groups: 8.21 versus 4.08 (ages 61-75) and 2.94 versus 1.84 (ages 75-90). Exposed had a higher risk of death (crude HR 1.73, 95% CI: 1.62-1.86) compared to unexposed.ConclusionsIn this register-based study we observed an association between inhaled anticholinergic use and reduced survival in dementia patients. This association is thought to be mainly driven by the underlying disease, COPD. Further studies are needed to clarify effects of inhaled anticholinergics on survival.},
}

@article {pmid41400119,
year = {2026},
author = {Basak, S and Colafrancesco, AM and Hernandez, RD and Wei, X and McMeekin, LJ and Dang, D and Simmons, M and Browning, JL and Noel, K and Zhou, F and Lund, FE and Saad, JS and Watsen, SG and Pickrell, AM and Cowell, RM and Olsen, ML},
title = {Novel Roles for the Ectoenzyme CD38 in the Maintenance of Transcriptional and Metabolic Homeostasis in Astrocytes.},
journal = {Glia},
volume = {74},
number = {2},
pages = {e70112},
doi = {10.1002/glia.70112},
pmid = {41400119},
issn = {1098-1136},
support = {R01NS124037/NH/NIH HHS/United States ; T32NS09.5775/NH/NIH HHS/United States ; 1S10RR026478/NH/NIH HHS/United States ; P30 CA013148/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; *Astrocytes/metabolism ; *ADP-ribosyl Cyclase 1/metabolism/genetics/deficiency ; *Homeostasis/physiology ; Mice ; Mice, Knockout ; Mice, Inbred C57BL ; NAD/metabolism ; Male ; *Membrane Glycoproteins/metabolism/genetics ; Brain/metabolism ; Mesencephalon/metabolism ; },
abstract = {CD38 is an ectoenzyme that converts NAD+ to NAM to help maintain bioenergetic homeostasis. CD38 dysregulation and gene variation is reported in neurodegenerative conditions such as Parkinson's disease (PD) and Alzheimer's disease (AD), highlighting the need to better understand CD38 biology within the brain. Here, we demonstrate enrichment of Cd38 in midbrain astrocytes and describe how CD38 deficiency influences brain metabolism, astrocytic gene expression, and bioenergetics. We demonstrate increased NAD content, decreased NAM content, and increased NAD/NAM in the midbrain and striatum of CD38-deficient (Cd38[-/-]) mice, indicating the dependence on CD38 for NAD to NAM conversion in the brain. RNA-sequencing of isolated astrocytes revealed numerous differentially expressed genes in Cd38[+/-] and Cd38[-/-] mice, with alterations in mitochondrial, metabolic, senescence-related, astrocyte reactivity, and other genes involved in PD and AD etiology. Furthermore, functional metabolic analysis of midbrain revealed changes in pyruvate oxidation, age-dependent increase of citrate synthase (CS) activity, and reduction of cytochrome c oxidase-to-CS ratio in Cd38 deficiency. These findings identify a novel role for astrocytes in the regulation of CD38-dependent NAD/NAM homeostasis in the brain and provide a framework for future studies evaluating the relationship between CD38 dysfunction, aging, and vulnerability of neuronal populations in neurodegenerative disease. Importantly, these studies underscore the necessity to better resolve the impact of CD38 deficiency on brain metabolism, considering ongoing clinical trials and discussions related to the use of CD38 modulators for the treatment of cancers, age-related decline, and neurodegenerative disease.},
}

Animals
*Astrocytes/metabolism
*ADP-ribosyl Cyclase 1/metabolism/genetics/deficiency
*Homeostasis/physiology
Mice
Mice, Knockout
Mice, Inbred C57BL
NAD/metabolism
Male
*Membrane Glycoproteins/metabolism/genetics
Brain/metabolism
Mesencephalon/metabolism

@article {pmid41399980,
year = {2025},
author = {Chu, F and Zhou, X and Ma, R and Liu, R and Liu, X and Zhu, K and Wang, Y and Wang, X and Li, Y and Zhang, S and Yin, T and Liu, Z},
title = {Piezo1-Targeted Magnetoacoustic Nanobubbles Rescue Alzheimer's Pathology by Electromechanical Neuromodulation and Amyloid-β Clearance.},
journal = {ACS nano},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsnano.5c13702},
pmid = {41399980},
issn = {1936-086X},
abstract = {Amyloid-β (Aβ) is considered a core pathological feature of Alzheimer's disease (AD), and its clearance efficiency is highly dependent on the function of the Piezo1 channel in microglia. However, the activity of Piezo1 is impaired under the pathological conditions of AD, and existing pharmacological strategies struggle to achieve precise targeted intervention in deep brain regions. To address these concerns, our research proposes a synergistic therapeutic paradigm leveraging transcranial magneto-acoustic stimulation (TMAS) to actuate microglial-Piezo1-targeted magnetic nanobubbles (PT-MNBs) for AD treatment. TMAS noninvasively focuses physical energy into deep brain lesion areas through a magnetoacoustic coupling field and drives PT-MNBs to generate responsive mechanical and electrical stimulation signals. PT-MNBs achieve microglia-specific anchoring through surface-modified phosphatidylserine, while conjugated anti-Piezo1 antibodies precisely deliver mechano-electrical stimulation signals to antibody-functionalized Piezo1 ion channels in microglial populations. This synchronously activates the mechanical- and voltage- sensitive domains of Piezo1 to recruit microglia to areas of inflammation and increase Aβ clearance, ameliorating synaptic plasticity impairment and ultimately reversing the pathological progression of AD. This dual-action mechanism achieves spatially precise manipulation of cellular mechanical and electrical activity in deep brain regions of AD mice and enhances Piezo1 function through precise energy delivery, enhancing their ability to clear Aβ plaques, opening an avenue for a noninvasive, deep-targeted physical stimulation-mediated nanoparticle synergistic therapy for AD.},
}

@article {pmid41399798,
year = {2025},
author = {Ghosh, S and Debnath, I and Bhunia, S and Nandi, S and Ashique, S and Nayak, A and Mallick, S and Basak, S},
title = {Decoding natural products for neuroprotection: Pathway networks and structural insights for drug development.},
journal = {Chinese herbal medicines},
volume = {17},
number = {4},
pages = {643-672},
pmid = {41399798},
issn = {2589-3610},
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis, are progressive disorders marked by neuronal dysfunction and death, driven by pathological mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, apoptosis, and protein misfolding. Despite scientific advances, current treatments remain largely palliative, underscoring the need for multitargeted therapeutic strategies. This narrative review synthesizes preclinical and clinical evidence to explore the neuroprotective potential of natural products, with a focus on their ability to modulate key molecular pathways implicated in NDs. A comprehensive literature search across Scopus, ScienceDirect, PubMed, MDPI, and Web of Science identified relevant studies. Bioactive compounds such as curcumin, resveratrol, ginsenosides, quercetin, and marine-derived molecules like fucoxanthin and phlorotannin demonstrated antioxidant, anti-inflammatory, anti-amyloidogenic, and mitochondrial-protective effects by modulating pathways including PI3K/Akt, NF-κB, and Nrf2/ARE, thereby mitigating neuronal damage and promoting cell survival. Natural products from diverse sources, including honey, ginseng, marine macroalgae, and cyanobacteria, exhibited broad-spectrum neuroprotective properties, with advances in nano-formulations improving bioavailability and brain penetration. Furthermore, emerging approaches such as gene-drug interaction studies and scaffold-based drug design offer promising avenues for enhancing clinical translation. While natural products provide a holistic, multitargeted approach to combat NDs, challenges related to bioavailability and therapeutic translation persist, necessitating future research that integrates advanced drug delivery systems, precision medicine, and synthetic modifications to develop innovative and effective treatment paradigms.},
}

@article {pmid41399730,
year = {2025},
author = {Zhang, Y and Chen, S and Yan, G and Zhang, Z and Amina, and Wang, T and Wang, S and Zhang, C and Sun, Y},
title = {MAPT mutation-induced behavioral variant frontotemporal dementia in an Asian patient: a multimodal biomarker case report resolving diagnostic challenges with Alzheimer's disease.},
journal = {Frontiers in genetics},
volume = {16},
number = {},
pages = {1645068},
pmid = {41399730},
issn = {1664-8021},
abstract = {BACKGROUND: The clinical phenotypic overlap between frontotemporal dementia (FTD) and Alzheimer's disease (AD) frequently leads to misdiagnosis, while biomarkers (e.g., Aβ-PET) and genetic testing provide critical differential diagnostic evidence. Although MAPT gene mutations represent common genetic etiologies of FTD, their occurrence in Asian populations remains underreported. Specifically, FTD caused by the MAPT IVS10 + 16C>T mutation shows limited documentation in Asian populations, with its phenotypic heterogeneity and treatment responses remaining poorly characterized.

METHODS: We present a case of FTD manifesting progressive memory decline, compulsive behaviors, and apathy. MRI revealed bilateral frontoparietotemporal atrophy with prominent medial temporal lobe and hippocampal involvement, initially misdiagnosed as AD. Subsequent Aβ-PET negativity emerged as a pivotal diagnostic turning point, and identification of a heterozygous MAPT mutation (IVS10 + 16C>T) confirmed behavioral variant FTD (bvFTD) diagnosis. Partial improvement in compulsive behaviors and verbal fluency was observed following memantine treatment. A literature review summarizes clinical characteristics of FTD associated with IVS10 + 16C>T mutations.

RESULTS: Comprehensive neuropsychological assessment, cranial MRI, and negative Aβ-PET excluded AD pathology. Genetic confirmation of MAPT IVS10 + 16C>T mutation established bvFTD diagnosis. Three-month memantine treatment reduced compulsive behaviors without cognitive improvement. Literature analysis indicates this mutation's rarity in Asian populations, typically presenting with behavioral abnormalities frequently misdiagnosed as AD.

CONCLUSION: This study rectified misdiagnosis of MAPT IVS10 + 16C>T-associated bvFTD through multimodal diagnostics, emphasizing the synergistic value of genetic testing and neuroimaging. Memantine's partial behavioral symptom alleviation suggests potential mutation-specific therapeutic efficacy requiring further validation. Future directions should optimize diagnostic protocols (e.g., cost-effective genetic screening) and address barriers to early diagnosis in Asian populations.},
}

@article {pmid41399578,
year = {2025},
author = {Gassull, A},
title = {Ethical Challenges in Managing a Displaced Neer III Humeral Head Fracture in an Undocumented Immigrant With Early Alzheimer's Disease: A Case Report.},
journal = {Cureus},
volume = {17},
number = {11},
pages = {e96805},
pmid = {41399578},
issn = {2168-8184},
abstract = {This report describes an 82-year-old undocumented Peruvian female immigrant presenting to the ED with right elbow pain and limited shoulder mobility, diagnosed with a displaced Neer III right humeral head fracture sustained two days prior. She had not clearly communicated shoulder pain to her family for two days post-injury, possibly due to early Alzheimer's disease, which may have impaired her ability to recognize or articulate the severity of her injury, illustrating the clinical-ethical intersection. Radiographic imaging confirmed the fracture with medial displacement, necessitating surgical intervention. Due to her undocumented status and lack of health insurance, she was required to pay the full cost of a reverse shoulder prosthesis (€24,000), which she could not afford. Her Alzheimer's-related dependency and absence of family support in Peru prevented seeking treatment abroad, resulting in discharge with a sling. Comprehensive blood tests ruled out metabolic contributors to her fall. This case highlights ethical challenges in healthcare access for undocumented immigrants, compounded by Alzheimer's-related communication and dependency issues, underscoring disparities and the need for equitable care. This case exemplifies how clinical vulnerability and legal status can intersect to create barriers in emergency and trauma care.},
}

@article {pmid41399419,
year = {2025},
author = {Chen, HW},
title = {Axial Spinal Traction as a Potential Modulator of Cerebrospinal and Glymphatic Circulation in Neurodegenerative Diseases: A Technical Report and Biomechanical Hypothesis.},
journal = {Cureus},
volume = {17},
number = {12},
pages = {e99153},
pmid = {41399419},
issn = {2168-8184},
abstract = {Impairment of glymphatic function contributes to the accumulation of metabolic and proteinaceous waste products implicated in neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and certain spinocerebellar ataxias. Pelvis-stabilized axial spinal traction (PSAST) is a biomechanical technique designed to produce brief, controlled cranio-caudal elongation of the vertebral column and spinal dural sac, potentially generating transient pressure gradients capable of influencing cerebrospinal fluid (CSF) dynamics and glymphatic circulation. The technique has been applied in the author's musculoskeletal practice for more than eight years without observed persistent or treatment-related adverse effects, although such practice-based experience does not constitute a formal safety evaluation. Improved sleep quality has been the most consistently reported patient-perceived response to PSAST, a clinically notable observation given the dependence of glymphatic function on consolidated slow-wave sleep. These practice-based observations provide preliminary, hypothesis-generating support for exploring whether controlled axial elongation may modulate cerebrospinal and glymphatic physiology. To the best of the author's knowledge, this report presents the first peer-reviewed technical description of a reproducible, whole-axis axial spinal traction procedure with defined force parameters intended to examine potential modulation of CSF and glymphatic circulation. The report outlines the PSAST protocol and its biomechanical rationale and safety considerations and proposes its potential relevance as a noninvasive, investigational approach for conditions associated with impaired glymphatic function.},
}

@article {pmid41399037,
year = {2025},
author = {Di Donna, MG and Motta, C and Bonomi, CG and Bernocchi, F and Ricci, F and Poli, M and Koch, G and Martorana, A},
title = {Reframing TDP-43 in Alzheimer's disease: From co-pathology to neurovascular culprit.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70988},
doi = {10.1002/alz.70988},
pmid = {41399037},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; *DNA-Binding Proteins/metabolism ; *Blood-Brain Barrier/metabolism/pathology ; Astrocytes/metabolism/pathology ; Endothelial Cells/metabolism/pathology ; *Brain/pathology/metabolism ; },
abstract = {Alzheimer's disease (AD) is widely recognized as a multifactorial disorder involving neurovascular and glial dysfunction beyond amyloid-β and tau pathology. In this Perspective, we synthesize recent evidence to propose a conceptual framework linking transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) to neurovascular unit (NVU) disruption in AD. Traditionally considered a neuronal co-pathology, TDP-43 also aggregates in astrocytes and endothelial cells, impairing blood-brain barrier (BBB) integrity, glymphatic clearance, and metabolic homeostasis. Endothelial TDP-43 loss disrupts β-catenin signaling and fibronectin, triggering vascular breakdown and neuroinflammation. Astrocytic perivascular aggregates correlate with reduced aquaporin-4 (AQP4) and CD146, further compromising clearance pathways. These vascular-glial mechanisms may accelerate AD progression and help explain clinical heterogeneity and limited therapeutic response in TDP-43-positive patients. We argue for the reclassification of TDP-43 as a potential upstream driver of disease progression. Such a shift would support the development of integrative biomarkers and precision treatment strategies targeting NVU dysfunction. HIGHLIGHTS: Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) may act as a driver of neurovascular dysfunction in Alzheimer's disease (AD). We propose reclassifying TDP-43 from co-pathology to upstream contributor. TDP-43 affects endothelial cells and astrocytes, disrupting blood-brain barrier (BBB) and clearance. Neurovascular unit (NVU) dysfunction links TDP-43 to inflammation, hypoperfusion, and cognitive decline. A vascular-glial model of AD opens new therapeutic and biomarker opportunities.},
}

Humans
*Alzheimer Disease/pathology/metabolism
*DNA-Binding Proteins/metabolism
*Blood-Brain Barrier/metabolism/pathology
Astrocytes/metabolism/pathology
Endothelial Cells/metabolism/pathology
*Brain/pathology/metabolism

@article {pmid41398677,
year = {2025},
author = {Wang, B and Wang, Y and Yang, F and Han, F and Li, K and Sun, K and Liang, P},
title = {The effect of repetitive transcranial magnetic stimulation on immediate and long-term cognitive functions in Alzheimer's dementia and mild cognitive impairment: a meta-analysis.},
journal = {Journal of neuroengineering and rehabilitation},
volume = {22},
number = {1},
pages = {262},
pmid = {41398677},
issn = {1743-0003},
support = {LGKCYLWS2022034//Key Project of Medical and health technology of Longgang District, Shenzhen/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; *Cognitive Dysfunction/therapy/psychology ; *Transcranial Magnetic Stimulation/methods ; *Cognition/physiology ; Randomized Controlled Trials as Topic ; Neuropsychological Tests ; Treatment Outcome ; Aged ; },
abstract = {BACKGROUND: Alzheimer's dementia (AD) and mild cognitive impairment (MCI) are characterized by progressive cognitive decline. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technology, has been widely used to improve cognition in AD and MCI. However, the impact of rTMS on immediate and long-term cognitive functions in AD and MCI, as well as the optimal stimulating parameters, need further clarification.

METHOD: Thirty-one randomized controlled trials were included to examine the effects of rTMS on immediate cognition (post-treatment cognition), while nine trials were specifically used to assess its impact on long-term cognition (follow-up cognition). All participants were tested on at least one of the neuropsychological scales of the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and Alzheimer's disease Assessment Scale-Cognitive Section (ADAS-Cog) to evaluate global cognitive outcomes of rTMS. The study followed the guidelines for meta-analysis of intervention studies and assessed the risk of bias of the included studies. Moderator analysis was used to examine factors that might affect treatment effect. Sensitivity analysis was used to evaluate stability of results. Meta-regression analysis was used to assess the interpretability of heterogeneity. Begg's and Egger's test and funnel plot were applied to assess publication bias.

RESULTS: The results demonstrated that rTMS significantly improved immediate cognition (SMD = 0.93, 95% CI = 0.64 to 1.22, p < 0.001) and long-term cognition (SMD = 0.42, 95% CI = 0.13 to 0.70, p = 0.004) across all patients (including AD and MCI). Moderator analysis revealed that targeting dorsolateral prefrontal cortex (DLPFC), using intensities of 80% or less of the motor threshold, total time of 800 min or more and stimulation sessions greater than 20 significantly enhanced immediate cognitive performance than their counterparts. In contrast, stimulation frequency, duration/session and patient type showed no significant impact on immediate cognition. For long-term cognition, differences in stimulation protocols had no influence on treatment effect for all patients.

CONCLUSION: rTMS had a positive effect on immediate and long-term cognition in AD and MCI, stimulation region, intensity, total time and number of sessions significantly improve immediate cognition. These findings suggest that rTMS has potential as a promising adjunctive treatment for AD and MCI.},
}

Humans
*Alzheimer Disease/therapy/psychology
*Cognitive Dysfunction/therapy/psychology
*Transcranial Magnetic Stimulation/methods
*Cognition/physiology
Randomized Controlled Trials as Topic
Neuropsychological Tests
Treatment Outcome
Aged

@article {pmid41398371,
year = {2025},
author = {Yoon, J and Ha, H and Lee, HW and Kim, S and Yu, YM and Chun, H},
title = {Potential beneficial effects of PD-1/PD-L1 blockade in Alzheimer's disease: a systematic review and meta-analysis of preclinical and clinical studies.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41398371},
issn = {1476-5578},
abstract = {BACKGROUND: Programmed cell death protein 1 (PD-1) and its ligand (PD-L1) are crucial in cancer immune evasion and in modulating neuroinflammation. Although PD-1/PD-L1 signaling is believed to modulate immune and neuronal responses, its role in AD pathophysiology remains unclear, with existing studies reporting inconsistent findings.

METHOD: This systematic review and meta-analysis investigated the effects of PD-1/PD-L1 blockade on AD-related pathology and cognitive behavior in preclinical studies. Additionally, we evaluated the impact of PD-1/PD-L1 inhibitors on cognitive outcomes in clinical studies involving cancer patients. Relevant research was systematically identified using the MEDLINE, Embase, CENTRAL, and Web of Science databases from their inception until July 31, 2025. Overall, 40 studies were included in this meta-analysis, conducted using R software.

RESULTS: Preclinical studies revealed that blockade of PD-1 signaling reduces amyloid-beta plaque burden, tau phosphorylation, and astrocyte reactivity in AD mouse models. These pathological improvements were accompanied by enhanced cognitive performance, whereas wild-type mice showed no significant cognitive changes under the same treatment, whereas wild-type mice showed no significant cognitive changes under the same treatment. Furthermore, clinical studies demonstrated the beneficial effect of PD-1 signaling inhibitors on cognitive function in patients with cancer.

CONCLUSIONS: PD-1/PD-L1 inhibition impacts AD pathology and cognitive function, suggesting its potential as a therapeutic development strategy for AD. Further studies are warranted to clarify the exact mechanisms, opening avenues for future therapies that modulate the PD-1/PD-L1 pathway for AD.},
}

@article {pmid41398125,
year = {2025},
author = {Huang, FW and Bello, ST},
title = {Role of Neuronal Cholecystokinin Receptor: An Emerging Therapeutic Target for Ameliorating Neurological Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {296},
pmid = {41398125},
issn = {1559-1182},
support = {11103220, 11101521, 11102422//Hong Kong Research Grants Council/ ; },
mesh = {Animals ; Humans ; *Receptors, Cholecystokinin/metabolism/antagonists & inhibitors ; *Nervous System Diseases/metabolism/drug therapy ; *Neurons/metabolism ; Cholecystokinin/metabolism ; },
abstract = {Neuronal cholecystokinin (CCK) is the most abundant neuropeptide in the mammalian brain and serves as a critical neuromodulator regulating the physiological states of animals. Previous research on CCK primarily focused on its roles in digestive function, satiety regulation, and emotional modulation, while its involvement in the development of brain diseases remains largely unexplored. Interestingly, recent studies have revealed that CCK-2 receptor antagonists have significant effects on neural modulation, suggesting a potential strategy for the treatment of brain disorders such as Alzheimer's disease, depression, and motor neuron disease, among others. To elucidate the neural effects of CCK on the progression of neurological disorders, we review the available evidence on the neuropeptide CCK in brain diseases at multiple levels and propose novel and complementary approaches to the treatment of brain diseases based on recent developments.},
}

Animals
Humans
*Receptors, Cholecystokinin/metabolism/antagonists & inhibitors
*Nervous System Diseases/metabolism/drug therapy
*Neurons/metabolism
Cholecystokinin/metabolism

@article {pmid41398046,
year = {2025},
author = {Heron, R and Amato, C and Monteiro-Black, B and Williams, RJ and Wood, W},
title = {Amyloid-beta induces distinct forms of cell death in different neuronal populations.},
journal = {Cell death and differentiation},
volume = {},
number = {},
pages = {},
pmid = {41398046},
issn = {1476-5403},
support = {22460/Z/21/Z//Wellcome Trust (Wellcome)/ ; 218627/Z/19/Z//Wellcome Trust (Wellcome)/ ; 218627/Z/19/Z//Wellcome Trust (Wellcome)/ ; MR/W019264/1//RCUK | Medical Research Council (MRC)/ ; 894935//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Skłodowska-Curie Actions (H2020 Excellent Science - Marie Skłodowska-Curie Actions)/ ; },
abstract = {Recent FDA approval for treating Alzheimer's disease (AD) with amyloid-beta (Aβ) immunotherapy is a historic breakthrough, which has rekindled widespread interest in understanding the molecular basis of Aβ toxicity. In this study, we developed a novel Drosophila model to investigate Aβ42-induced pathologies in vivo and in real time. Strikingly, we unveiled compelling evidence that secreted Aβ42 affects different neurons in distinct ways-both in susceptibility to Aβ42 deposition and in the mode of cell death triggered. Additionally, we observed altered larval crawling behaviour which-remarkably-could be recovered by inhibiting ferroptotic cell death with small molecule inhibitors. Collectively these findings showcase this as a powerful new model for investigating Aβ toxicity in AD and identifying novel treatment strategies.},
}

@article {pmid41397735,
year = {2025},
author = {Zong, G and Li, R and Jiang, Y and Chen, Z and Yan, S and Yi, Z and Ren, X and Jia, B},
title = {[Two cases of urinary retention in patients with Alzheimer's disease with agitation treated by acupuncture].},
journal = {Zhongguo zhen jiu = Chinese acupuncture & moxibustion},
volume = {45},
number = {12},
pages = {1822-1824},
doi = {10.13703/j.0255-2930.20250804-k0002},
pmid = {41397735},
issn = {0255-2930},
mesh = {Humans ; *Alzheimer Disease/complications/therapy/psychology ; *Acupuncture Therapy ; *Urinary Retention/therapy/etiology ; Male ; Female ; Aged ; Acupuncture Points ; *Psychomotor Agitation/therapy/complications ; },
abstract = {This article reports 2 cases of urinary retention in Alzheimer's disease with agitation treated by acupuncture. Based on patients' clinical symptoms, the etiology and pathogenesis were determined, and acupuncture was applied to Baihui (GV20), Sishencong (EX-HN1), Shenting (GV24), and bilateral Ciliao (BL32), Zhongliao (BL33), Fengchi (GB20), Taiyang (EX-HN5), etc. to regulate the mind and promote water metabolism. The positive and negative electrodes of the SDZ-Ⅴ type electroacupuncture device were attached to ipsilateral Ciliao (BL32), Zhongliao (BL33) respectively, with continuous wave, at the frequency of 15 Hz, and the current of 3 to 10 mA, depending on patients' tolerance. The needles were retained for 20 min. The treatment was delivered once every other day, 3 interventions a week and 12 interventions as 1 course. Both patients reported the micturition desire after 1 intervention with acupuncture and the catheter was removed on the same day. The urination was ameliorated without dysuresia after 1-2 courses of treatment, and the agitated behavior was alleviated. It can be the reference for the clinical treatment of urinary retention in patients with Alzheimer's disease with agitation.},
}

Humans
*Alzheimer Disease/complications/therapy/psychology
*Acupuncture Therapy
*Urinary Retention/therapy/etiology
Male
Female
Aged
Acupuncture Points
*Psychomotor Agitation/therapy/complications

@article {pmid41397578,
year = {2025},
author = {Wang, X and Wang, X and Zhao, C and Zhao, H and Wang, P and Song, T},
title = {Enhancement of cognitive behavior and hippocampal neural oscillations by rhythmic unipolar pulsed magnetic stimulation in 5xFAD Alzheimer's disease mice.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {115995},
doi = {10.1016/j.bbr.2025.115995},
pmid = {41397578},
issn = {1872-7549},
abstract = {Alzheimer's disease (AD) imposes a heavy burden on families and society. Rhythmic magnetic stimulation has emerged as a promising non-invasive therapy to mitigate AD-related cognitive decline. In this study, we applied a rhythmic unipolar compound pulsed magnetic field (cPMF; carrier frequency: 40Hz, repetition rate: 5Hz, magnetic flux density: 0-20 mT) incorporating both theta and gamma rhythms to evaluate its effects on behavior and neural oscillations in AD mice and to explore the underlying mechanisms. 5xFAD mice received unipolar cPMF stimulation for 1h/d over 8 consecutive weeks. Learning and memory were assessed using the novel object recognition (NOR) and the Morris water maze (MWM) tests. In NOR test, unipolar cPMF-treated mice showed a higher cognitive index in test phase 2, and in MWM test, exhibited shorter escape latencies in the training trial and spent less time to first cross the precise former platform location with a higher crossing frequency over this target area in the probe trial. Local field potentials (LFPs) in the hippocampal CA1 area were recorded via in vivo electrophysiology. LFP analysis showed that unipolar cPMF treatment enhanced power of cognitive-related neural oscillations and strengthened theta-gamma phase-amplitude coupling. RNA sequencing analysis further indicated that unipolar cPMF-treated mice exhibited differential gene expression in molecular function and multiple neurotransmitter synaptic signaling pathways. In conclusion, unipolar cPMF might improve cognitive function in 5xFAD mice by modulating cognitive-related neural oscillations. These findings could provide experimental support for the low-intensity pulsed magnetic stimulation as a potential therapeutic strategy for AD.},
}

@article {pmid41397211,
year = {2026},
author = {Satyadev, N and Piura, YD and Tipton, PW and Dunham, SR and Morris, JC and Geschwind, MD and Brier, M and Graff-Radford, NR and Day, GS},
title = {Standardizing "Rapid": Applying the Clinical Dementia Rating to Define Rapidly Progressive Dementia.},
journal = {Neurology},
volume = {106},
number = {1},
pages = {e214439},
doi = {10.1212/WNL.0000000000214439},
pmid = {41397211},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; Disease Progression ; Aged ; *Dementia/diagnosis ; Aged, 80 and over ; Retrospective Studies ; Middle Aged ; *Mental Status and Dementia Tests/standards ; },
abstract = {BACKGROUND AND OBJECTIVES: Rapidly progressive dementia (RPD) accounts for 3%-4% of dementia cases yet presents a disproportionate clinical challenge given the wide differential diagnosis and the need to quickly identify potentially treatment-responsive causes. The lack of a standardized definition of RPD challenges generalization of published findings and precludes multisite studies. We sought to determine whether a standardized definition, based on the Clinical Dementia Rating (CDR), could reliably distinguish individuals with a broad spectrum of causes of RPD early in the symptomatic course.

METHODS: RPD was defined as dementia (global CDR ≥1) developing within 1 year or incapacitation (global CDR ≥2) within 2 years of symptom onset. Patients with suspected RPD were referred from inpatient and outpatient settings at Mayo Clinic in Florida (Jacksonville, FL) and Washington University in St. Louis (Saint Louis, MO) and prospectively evaluated (RaPID cohort). Retrospective data from participants assessed across 46 research centers were also analyzed (National Alzheimer's Coordinating Center [NACC] data set). Characteristics and rates of progression (main outcome) were compared between typically progressive and RPD. Univariable and multivariable analyses were performed using Mann-Whitney U/Kruskal-Wallis (continuous) and Fisher exact/χ[2] tests (binary), respectively. Our definition of RPD was compared against definitions identified through a scoping review conducted using a validated 6-stage approach.

RESULTS: In the RaPID cohort, 185 of 248 (74.6%) patients met our CDR-based RPD definition (median [range] age-at-symptom onset: 68.8 years [22.0-90.7]; 45.4% female). Autoimmune (55/185, 29.7%), neurodegenerative (51/185, 27.6%), and prion diseases (35/185, 18.9%) predominated. Among 20,418 NACC participants with cognitive impairment, 836 (4.1%) met our RPD definition (median [range] age-at-symptom onset: 74 years [24-103]; 57.1% female). Neurodegenerative diseases predominated, especially Alzheimer disease (485/836, 58.0%). Individuals with RPD declined substantially faster (ΔCDR sum-of-boxes/year: RaPID, 14.4 ± 5.3 vs 4.3 ± 4.3, p < 0.001; NACC, 6.7 ± 3.1 vs 1.7 ± 1.4, p < 0.001). Our scoping review identified 22 studies that applied 10 distinct definitions of RPD. Uniquely, our CDR-based definition clearly distinguished individuals with a broad spectrum of causes of RPD, assessed across multiple sites/settings, supporting early diagnosis with minimal resource requirements.

DISCUSSION: The CDR-based definition of RPD effectively identified individuals with a broad spectrum of causes of RPD early in the symptomatic course. The need for training and time to reliably administer the CDR may limit application of the proposed definition of RPD. Validation in additional cohorts is required to support generalizability.},
}

Humans
Female
Male
Disease Progression
Aged
*Dementia/diagnosis
Aged, 80 and over
Retrospective Studies
Middle Aged
*Mental Status and Dementia Tests/standards

@article {pmid41396874,
year = {2025},
author = {Zu, J and Li, C and Cui, M and Liu, X and Pan, Z and Li, X and Zhang, F and Gentz, J and Mitteregger-Kretzschmar, G and Herms, J and Shi, Y},
title = {Pioglitazone attenuates complement-mediated microglial synaptic engulfment in an Alzheimer's disease model.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf462},
pmid = {41396874},
issn = {1460-2156},
abstract = {Synaptic loss is an early hallmark of Alzheimer's disease (AD), predominantly driven by aberrant microglial reactivity. Pioglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist with anti-diabetic properties, has been shown to suppress microglial activity and improve cognitive performance in both AD models and clinical studies. However, whether its neuroprotective effects involve direct modulation of synaptic architecture remains unclear. Here, using longitudinal in vivo two-photon imaging, multi-channel immunohistochemistry, super-resolution confocal microscopy, and 3D reconstruction techniques in an AD mouse model, we analysed synaptic and microglial interactions. We show that a 4-week pioglitazone treatment preserves dendritic spine density and enhances spine stability over time. Mechanistically, pioglitazone reduces synaptic C1q deposition, thereby limiting complement-mediated microglial synaptic engulfment and attenuating synapse loss. These findings identify pioglitazone as a modulator of complement-dependent microglial synaptic pruning and support its therapeutic potential in preserving synaptic integrity during early AD pathogenesis.},
}

@article {pmid41396614,
year = {2025},
author = {Brown, CA and Mundada, NS and Cousins, KAQ and Sadeghpour, N and Lyu, X and McGrew, E and Korecka, M and Chen-Plotkin, A and Xie, L and Wisse, LEM and Detre, JA and McMillan, CT and Lee, EB and Nasrallah, IM and Das, SR and Mechanic-Hamilton, D and Yushkevich, PA and Shaw, LM and Wolk, DA and , },
title = {Evaluation of Copathology and Clinical Trajectories in Individuals With Tau-Clinical Mismatch.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2025.4974},
pmid = {41396614},
issn = {2168-6157},
abstract = {IMPORTANCE: Even within individuals who are amyloid positive, clinical symptoms can be impacted by Alzheimer pathology, other pathologic proteins, and cognitive reserve or resilience. Understanding how each of these factors contributes to a patient's clinical presentation is crucial for prognosis and treatment decisions in the era of disease-modifying therapies.

OBJECTIVE: To evaluate tau-clinical mismatch as a means to identify those more likely to harbor copathology and/or exhibit resilience to Alzheimer pathology.

This was a longitudinal, observational cohort study conducted from 2004 to 2024. The setting included multiple academic medical centers in the US participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI) or Penn Alzheimer's Disease Research Center (Penn-ADRC). Included in the analysis were individuals with clinical assessment and measures of either tau positron emission tomography (tau-PET) or phosphorylated tau 217 (p-tau217) who were selected from individuals positive for amyloid β (Aβ+) in the ADNI cohort (aged 55-95 years) and the Penn-ADRC cohort (aged 54-92 years).

EXPOSURES: Clinical assessment (Clinical Dementia Rating Sum of Boxes [CDR-SB]) and tau burden (tau-PET or p-tau217) for mismatch group classification.

MAIN OUTCOMES AND MEASURES: Cross-sectional measures of neurodegeneration (medial temporal lobe volume and thickness, cortical thickness, TAR DNA-binding protein 43 [TDP-43] imaging signature), α-synuclein cerebrospinal fluid seed-amplification assay, and longitudinal CDR-SB.

RESULTS: A total of 365 participants (mean [SD] age, 75.4 [7.9] years; 192 female [52.6%]) in the ADNI tau-PET group and 524 participants (mean [SD] age, 77.1 [7.9] years; 268 male [51.1%]) in the ADNI p-tau217 group were selected from the 998 individuals who were Aβ+ in the ADNI cohort and used to generate tau-clinical mismatch models with 55.6% to 57.1% classified as canonical (CDR-SB commensurate to tau), 23.7% to 24.7% as resilient (CDR-SB < tau), and 19.3% to 19.7% as vulnerable (CDR-SB > tau). Vulnerable groups had evidence of greater likelihood of copathology, with TDP-43 neurodegeneration patterns and α-synuclein positivity. Mismatch groups showed diverging clinical trajectories with earlier cognitive impairment in vulnerable groups and later impairment in resilient individuals. Similar findings were seen when applied to an independent dataset of 244 individuals (mean [SD] age, 73.7 [6.8] years; 139 female [57.0%]) of the 248 who were Aβ+ in Penn-ADRC cohort. Finally, these models were applied to a cohort receiving antiamyloid therapy to show the utility of this method for predicting individual cognitive trajectories during therapy.

CONCLUSION AND RELEVANCE: Results of this cohort study suggest that tau-clinical mismatch identified individuals more likely to have an accelerated disease course due to the presence of copathology and those exhibiting greater cognitive resilience to disease pathology. These models provide an important tool that can be implemented in clinical practice to provide improved individualized prognosis and, potentially, monitoring of response to disease-modifying therapy.},
}

@article {pmid41396413,
year = {2025},
author = {Zuliani, G and Brombo, G and Romagnoli, T and Polastri, M and Dario, FDP and Zuin, M},
title = {Effectiveness of acetylcholinesterase inhibitors and memantine in patients affected by severe dementia.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41396413},
issn = {2509-2723},
abstract = {The efficacy of acetylcholinesterase inhibitors (AChEI) and memantine (ME) in severe dementia remains uncertain, and real world data are limited. We evaluated the progression of cognitive decline and mortality rates in a cohort of outpatients with severe dementia treated with AChEI and/or ME or not treated, from the National Alzheimer's Coordinating Center Uniform Data Set (NACC-UDS). Overall, 703 patients (mean age:78.3 ± 7.2 years; females:56.1%) with severe dementia (Mini-Mental State Examination-MMSE ≤ 10/30) were included [407 late-onset Alzheimer's disease (LOAD), 126 Lewy body dementia (LBD), 170 vascular dementia (VD)]. Patients were grouped by treatment status: untreated (AChEI - /ME - ; n.70), AChEI only (AChEI + ; n.294), ME only (ME + ; n.215), combined therapy (AChEI + /ME + ; n.124). During follow-up (mean:1.7 ± 0.3 years; range:0.2-2.9 years) the mean MMSE scores declined by - 1.7 points (Standard Deviation: -1.55 to -1.9) in AChEI - /ME - (p for trend:0.001), - 1.5 points (-1.55 to -1.9) in AChEI + (p:0.001), - 0.7 points (-0.5 to -0.9) in ME + (p:0.09), while it increased by + 0.7 points (+ 0.4 to + 1.0) in AChEI + /ME + (p:0.001). Survival rates were 8% in AChEI - /ME - , 10% in AChEI + , 28% in ME + , and 49% in AChEI + /ME + . In Cox proportional hazards analysis (age and sex adjusted), AChEI + /ME + exhibited a 39% reduction in total mortality compared with no treatment (HR:0.61; 95%CI:0.49-0.77; p < 0.001), ME + displayed a 22% reduction (HR:0.78; 95%CI:0.65-0.94; p:0.007), while AChEI + showed no association (HR:0.97; 95%CI:0.80-1.18; p:0.75). When the Cox proportional hazards models were stratified by dementia subtype, consistent significant patterns were observed in LOAD and LBD. In this real-world cohort of older adults with severe dementia, the combination therapy (ME + AchEI) seems to be associated with the best outcomes, including a stabilization of cognitive function and reduced total mortality.},
}

@article {pmid41396167,
year = {2025},
author = {Robinson, L and Bray, J and Melis, V and Harrington, CR and Wischik, CM and Riedel, G},
title = {Effects of hydromethylthionine mesylate and rivastigmine in a pharmacological mouse model of Alzheimer's disease.},
journal = {Behavioural pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1097/FBP.0000000000000865},
pmid = {41396167},
issn = {1473-5849},
support = {PAR 1577//WisTa Laboratories Ltd/ ; },
abstract = {The results from clinical trials have indicated that the tau aggregation inhibitor hydromethylthionine mesylate (HMTM) produces disease-modifying effects in Alzheimer's disease (AD) patients when administered alone, but less of an effect when administered in conjunction with cholinesterase inhibitors (ChEIs). The use of ChEIs for AD has been supported by their ability to reverse scopolamine-induced cognitive impairments in rodents reminiscent of those seen in AD patients. We have previously shown that another tau aggregation inhibitor, methylthionine chloride (MTC), is able to reverse scopolamine-induced deficits in spatial learning and memory. The objective here was to determine the symptomatic efficacy of HMTM and rivastigmine, alone or in combination, in a scopolamine model of AD. Female NMRI mice were treated systemically with scopolamine (0.5 mg/kg) or vehicle in combination with ChEI rivastigmine (0.5 mg/kg) or HMTM (5 or 15 mg/kg) daily before assessment of spatial learning and memory performance in a reference memory task in the water maze. Systemic administration of scopolamine induced significant impairments in the spatial learning of the mice compared to vehicle treatment. These deficits were reversed by treatment with HMTM at both doses and with rivastigmine when given alone. Furthermore, coadministration of rivastigmine with HMTM ameliorated the impairments induced by scopolamine. These findings extend our previous observations with MTC and confirm that HMTM also has a dual mode of action, disease modification through tau aggregation inhibition, but also having symptomatic effects through its normalisation of cholinergic activity.},
}

@article {pmid41396015,
year = {2025},
author = {Leng, L and Liao, Z and Lu, P and Sun, Y and Weng, Q and Fan, W and Zhu, H and Wu, W and Liu, P and Liu, X and Zhang, K and Wang, W and Luo, B and Wang, Z and Peng, G},
title = {Real-world experience with baseline characteristics and safety of lecanemab for Alzheimer's disease in Eastern China.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251406619},
doi = {10.1177/13872877251406619},
pmid = {41396015},
issn = {1875-8908},
abstract = {BackgroundLecanemab reduces amyloid levels and modestly slows cognitive decline in a large cohort of early Alzheimer's disease (AD) but lacks real-world safety data in Chinese population.ObjectiveThe real-world study aims to analyze baseline characteristics and preliminary safety of lecanemab for AD in Zhejiang Province, and to evaluate the efficacy of plasma biomarkers for patient screening.MethodsThis multi-center study included 190 patients with AD in Zhejiang Province, who completed baseline assessments and received lecanemab treatment with follow-up.ResultsThe study included 176 participants with early AD and 14 moderate. In the early AD (mean age 68.04 years, Mini-Mental State Examination 20.03 and Montreal Cognitive Assessment 14.93), 124 (70.5%) participants were female, and 127 (72.1%) were junior high school education level or less. APOE4 heterozygote was predominant (48.9%). Logistic regression for distinguishing early AD from the Aβ negative cognitively unimpaired populations showed that p-Tau 217 independently provided better classification efficacy (area under the curve = 0.9983, p < 0.0001). In the early AD, 29 (16.5%) participants experienced infusion-related reactions (IRR) after the first-dose lecanemab, and amyloid-related imaging abnormalities (ARIA) were identified in 17 patients (9.7%), while 3 (21.4%) with IRR and none ARIA observed in the moderate AD.ConclusionsThe real-world lecanemab cohort had more females, lower educational level, and higher disease burden compared with the clinical trial cohort. Overall lecanemab exhibited a manageable short-term safety profile with no measurable cognitive efficacy. Extensive monitoring and management are required for ARIA of clinically importance. The plasma p-Tau 217 showed high accuracy for early AD screening.},
}

@article {pmid41394556,
year = {2025},
author = {Seto, M and Klinger, HM and Clifton, M and Janve, VA and Brown, JA and Birkenbihl, C and Coughlan, G and Townsend, DL and Wang, TC and Properzi, M and Hanseeuw, B and Chhatwal, J and Yang, HS and Rissman, RA and Aisen, P and Cuppels, M and Donohue, MC and Raman, R and Johnson, KA and Sperling, RA and Dumitrescu, L and Hohman, TJ and Buckley, RF},
title = {Blood-based Transcriptomics Reveal Sex- and Amyloid-Modulated Biology of Plasma pTau217 in Preclinical Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.21.689770},
pmid = {41394556},
issn = {2692-8205},
abstract = {Plasma pTau217, an emerging Alzheimer's disease (AD) biomarker, may reflect a synaptic response to β-amyloid (Aβ) plaques before cortical tangle formation, but the broader biological processes at play remain unclear. Using whole blood RNAseq, we sought to identify gene expression associated with plasma pTau217 and to determine whether APOE ε4, sex, and neocortical Aβ-PET burden further amplify these associations in 724 participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Studies. 1,540 genes were moderated by Aβ-PET, and 772 genes were moderated by both Aβ-PET and sex. Our findings include genes previously associated with AD (e.g., TREML2) and implicate biological functions such as chromatin remodeling, lipid signaling, and RNA processing that interact with Aβ-PET and sex to impact plasma pTau217. Our results underscore the complexity of molecular mechanisms that can be linked to plasma pTau217, particularly in the context of elevated Aβ-PET.},
}

@article {pmid41394158,
year = {2025},
author = {Li, Y and Zhang, Y and Liu, M and Dawuti, T and Chen, X and Xiao, H},
title = {Polyphenol-rich Morus nigra L. extract mitigates neuroinflammation and cognitive impairment through gut-brain axis modulation in an Alzheimer's disease rat model.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1695768},
pmid = {41394158},
issn = {1663-9812},
abstract = {BACKGROUND: The gut-brain axis (GBA) has emerged as a critical pathway in the pathogenesis of Alzheimer's disease (AD), offering a potential target for dietary interventions. This study aimed to explore the neuroprotective effects of a polyphenol-enriched extract from Morus nigra L. fruits (MMF) in an AD rat model, focusing on gut-brain communication.

METHODS: AD-like pathology was induced in rats using a combination of D-galactose and aluminum chloride, followed by a 10-week MMF treatment. Cognitive performance was evaluated using the Morris water maze, and brain Aβ1-42 accumulation and neuroinflammation (Iba1, GFAP) were assessed. Multi-omics approaches, including 16S rDNA sequencing and untargeted colonic metabolomics, were applied.

RESULTS: MMF treatment significantly enhanced spatial memory, reduced hippocampal Aβ burden, and attenuated glial activation. Furthermore, MMF restored gut microbial diversity and increased the abundance of short-chain fatty acid-producing Firmicutes taxa, which were inversely correlated with inflammation. Metabolomics analysis revealed that MMF modulated bile acid and lipid metabolic pathways, with β-muricholic acid, DHA, and ergosterol identified as key effectors.

CONCLUSION: MMF alleviates AD pathology through modulation of the gut microbiota and metabolic reprogramming, suggesting a promising microbiota-targeted strategy for AD prevention.},
}

@article {pmid41394066,
year = {2025},
author = {Rubiño-Díaz, JÁ and Zapata-Moreno, M},
title = {Highly sensitive early-onset Alzheimer's disease: a case report.},
journal = {Frontiers in psychology},
volume = {16},
number = {},
pages = {1688924},
pmid = {41394066},
issn = {1664-1078},
abstract = {BACKGROUND: Early-onset Alzheimer's disease (EOAD) is an atypical syndrome that can be confused with other neurodegenerative diseases. This disease presents before the age of 65, with symptoms that generally affect executive functions, praxis, and visuoperceptual abilities, as opposed to episodic memory. Highly sensitive individuals present the temperament trait of sensory processing sensitivity, which is characterized by a differential susceptibility compared to other individuals. Neuropsychological evaluation should involve a holistic and integrative person-centered care approach for optimal treatment and disease progression.

CASE SUMMARY: A highly sensitive 54-year-old individual was diagnosed with EOAD at age 47 in 2017. Neuropsychological follow-up was conducted for 6 years. Initial neuropsychological testing revealed a cognitive pattern with impairments in executive functions, attention, and visual perception, the advancement of which led to a progressive deterioration in daily, occupational, and social functioning. During this period, he received psychotherapy from a psychologist specializing in neuropsychology and high sensitivity, using a holistic and integrative approach. Initially, sessions were held twice a week throughout the first year of consultation and, subsequently, continued at the patient's home and in his usual context, using a completely ecological perspective and consisting of person-centered care. In 2022, the patient, aged 59, was admitted to a nursing home. This situation, outside his usual environment, without autobiographical references and his own life story, led to accelerated deterioration, with the patient ultimately dying at age 60, in 2023.

CONCLUSION: The patient with highly sensitive EOAD was followed for 6 years by a psychologist specializing in neuropsychology and high sensitivity. Neuropsychological intervention was maintained with a holistic and integrative person-centered approach using the unmet needs model to address cognitive, psychological, and functional levels. Follow-up with this approach could be key to slowing the disease and ensuring patient satisfaction throughout the entire progression of the illness. Greater visibility into unusual cases like this will enable psychology professionals to be vigilant for timely differential and diagnostic testing, which will significantly impact the treatment and progression of the illness, ultimately influencing quality of life and well-being through an optimal neuropsychological approach.},
}

@article {pmid41393110,
year = {2025},
author = {Kim, EH and Lee, YJ and Moon, YS and Kwon, OD and Kwon, DR},
title = {Evaluation of microcurrent as an adjunct to donepezil therapy in an Alzheimer's disease mouse model: a pilot study.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1689593},
pmid = {41393110},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder due to Aβ plaque accumulation, followed by loss of synapses and decline in cognitive abilities. Donepezil is currently one of the standard pharmacological treatments for Alzheimer's disease. Recently, microcurrent (MC) therapy has emerged as a non-pharmacological adjunct for AD management. Recently, microcurrent therapy emerged as a non-pharmacological alternative to treat AD.

OBJECTIVE: The study investigates the therapeutic outcomes of the MC as an adjuvant to donepezil in mitigating cognitive dysfunction in the transgenic mouse model (5XFAD).

METHODS: Transgenic 5xFAD mice were assigned to the control, donepezil, MC, or MC + donepezil (combination) groups. Behavioral performance was assessed using the novel object recognition (NOR) and radial arm maze (RAM) tests. Amyloid burden, glial activation, cytokine expression, apoptotic signaling, and intracellular pathways (PI3K-AKT, AMPK, and JAK2/3) were analyzed by immunohistochemistry and Western blotting.

RESULTS: Combined treatment with donepezil and microcurrent showed a trend toward improved cognitive performance and reduced pathology compared to donepezil alone, although these differences were not statistically significant. Aβ plaque burden in the cortex and the hippocampus was reduced by approximately 68%, thereby exceeding reductions observed with either treatment alone. Microglial and astroglial activation (Iba1, GFAP, and CD68) and pro-inflammatory cytokines (TNF-α and IL-1β) were reduced in both the donepezil and combination groups compared with untreated 5xFAD mice, with no significant difference between 5xD and 5xD + MC. Apoptotic markers (cleaved caspase-3 and cleaved PARP) were significantly reduced in both treatment groups compared with untreated controls but not significantly different between donepezil and combination therapy. At the molecular level, both donepezil and combination therapy activated PI3K-AKT and AMPK signaling and increased inhibitory phosphorylation of GSK-3β compared with untreated 5xFAD mice; no significant difference was observed between the two treatment groups.

CONCLUSION: Donepezil combined with microcurrent therapy showed comparable efficacy to donepezil alone, with numerical trends toward further improvement in cognitive function and pathology, but without statistically significant differences. Both treatments reduced Aβ burden, attenuated glial activation, and modulated survival-related pathways to a similar extent. These findings support a multi-target therapeutic strategy and highlight the translational potential of integrating microcurrent therapy with standard pharmacological treatment for AD.},
}

@article {pmid41392105,
year = {2025},
author = {Barani, M and Zargari, F and Mirinejad, S and Madani, F and Hajinezhad, MR and Sargazi, S},
title = {Ginsenoside Rg3-encapsulated pegylated niosomes exhibit multimodal therapeutic potential in Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-32528-3},
pmid = {41392105},
issn = {2045-2322},
support = {4021411//National Institute for Medical Research Development/ ; },
abstract = {Ginsenoside Rg3 (GRg3), a bioactive compound extracted from ginseng, has demonstrated the ability to inhibit Aβ production and deposition. In this study, PEGylated GRg3-loaded niosomes were developed and characterized for potential AD treatment. Their efficacy was assessed using in vitro and in vivo models, as well as molecular dynamics simulations of self-assembly. Our formulation achieved a relatively high encapsulation efficiency of 83.02% and a controlled release profile, with 75.73% of the drug released over 48 h. In vitro, co-administration of Aβ with free or PEGylated GRg3-loaded niosomes markedly reduced the levels of Total Antioxidant Capacity, Malondialdehyde (MDA), and caspase-3 gene expression compared to the Aβ-only group. In vivo evaluations revealed that treatment with the niosomal formulation did not significantly alter behavioral parameters, MDA levels, or Superoxide Dismutase activity. However, catalase activity was significantly higher than in the control group. Histopathological and immunohistochemical analyses showed reduced neurovascular damage and preservation of blood-brain barrier (BBB) and hippocampal integrity in the treated group. MD simulations confirmed the spontaneous self-assembly of surfactant molecules into a bilayer structure with successful incorporation of GRg3. Our findings underscore the potential of PEGylated niosomes as efficient nanocarriers for GRg3 delivery in the AD treatment.},
}

@article {pmid41391900,
year = {2026},
author = {Ehret, F and Rogers, CL and Fontanesi, J and Wilson, GD and Chitti, BS and Starner, J and Sidiqi, B and Goenka, A and Schulder, M and Bruynzeel, AME and Verhoeff, JJC and MacDonagh, AC and Park, HI and Shih, HA and Kleinberg, L},
title = {Radiation Therapy for Non-Malignant Central Nervous System Tumors, Disorders, and Illnesses - Current Applications and Future Directions.},
journal = {Seminars in radiation oncology},
volume = {36},
number = {},
pages = {77-94},
doi = {10.1016/j.semradonc.2025.08.005},
pmid = {41391900},
issn = {1532-9461},
mesh = {Humans ; *Central Nervous System Neoplasms/radiotherapy ; *Mental Disorders ; },
abstract = {Radiation therapy has a central role in the treatment of various malignant central nervous system tumors, including gliomas, high-grade meningiomas, and brain metastases. This also applies to a plethora of non-malignant central nervous system lesions, such as vestibular schwannomas and arteriovenous malformations, and, in specific situations, for selected functional and psychiatric disorders. In patients with these conditions, the goal of radiation therapy is generally to preserve and stabilize function. In addition, as these illnesses, with some exceptions such as arteriovenous malformations, are rarely life-threatening, the risks of radiation therapy must be interpreted in a different context than for patients with malignancy. Given the continuous and growing interest in the use of radiation therapy for non-malignant tumors and functional conditions, this review summarizes the current and future directions in central nervous system applications, addressing its use for the management of vestibular schwannomas, arteriovenous malformations, trigeminal neuralgia, tremor, Alzheimer's disease, and other psychiatric conditions, such as obsessive-compulsive disorder, addiction, and eating disorders.},
}

Humans
*Central Nervous System Neoplasms/radiotherapy
*Mental Disorders

@article {pmid41391736,
year = {2025},
author = {Chen, H and Zhang, Z and Yi, W and Wang, N and Dong, X and Xing, Y and Liu, Q and Wu, Y and Ma, X},
title = {Bone-brain crosstalk: emerging roles of osteocalcin in central nervous system disorders.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.12.028},
pmid = {41391736},
issn = {1873-7544},
abstract = {Despite significant advancements in understanding the pathogenesis of various central nervous system (CNS) disorders, challenges remain in the early intervention and targeted therapies for common neurodegenerative and psychiatric conditions such as Parkinson's disease (PD), Alzheimer's disease (AD), anxiety, depression, and strokes. Recent studies have increasingly focused on the interaction between the peripheral and central nervous systems, emphasizing the regulatory influence of peripheral mechanisms on CNS disorders. This evolving perspective paves the way for innovative treatment strategies for CNS diseases, with the bone-brain axis emerging as a key regulatory pathway. This axis was first systematically proposed to highlight the role of bone-derived hormones in brain function. Importantly, bone tissue extends its functions beyond mere structural support and movement; it secretes molecules like osteocalcin (OCN) that influence neuronal and glial cell activities. This interaction is vital for regulating multiple CNS processes, including mood, cognition, inflammation, and the formation and differentiation of myelin. Upon release from bone tissue, OCN enters the bloodstream and affects peripheral organs via the Gprc6a receptor, while also crossing the blood-brain barrier to interact with receptors such as Gpr158 and Gpr37 in specific brain areas. This intra-brain interaction significantly impacts the progression and prognosis of various CNS disorders. This article undertakes a comprehensive analysis of OCN modulation in CNS disorders and its underlying mechanisms, laying the groundwork for further exploration of its clinical applications and suggesting new research avenues and therapeutic strategies for CNS diseases.},
}

@article {pmid41391511,
year = {2025},
author = {Gawai, M and Nistane, N and Tatode, AA and Qutub, M and Umekar, MJ and Premchandani, T and Taksande, JB},
title = {Transforming Anti-Alzheimer's therapy by targeting endogenous receptorrial system through ligand-conjugated Nanoformulations.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102994},
doi = {10.1016/j.arr.2025.102994},
pmid = {41391511},
issn = {1872-9649},
abstract = {Alzheimer's Disease (AD) is the most prevalent neurodegenerative disorder, contributing to the majority of dementia cases in the elderly globally. Characterized by progressive cognitive decline, AD is associated with complex neuropathological changes, including the accumulation of amyloid-beta (Aβ) plaques and tau tangles, synaptic loss, and neuroinflammation. One of the significant challenges in treating AD is the blood-brain barrier (BBB), which prevents many therapeutic agents from reaching the brain. Despite advancements in understanding AD's pathology, limited treatment options are available, largely due to the inability of conventional drugs to effectively target the brain. Ligand-conjugated nanoparticles (NPs) are promising for targeted drug delivery to the brain. These NPs, engineered with ligands that can bind to specific receptors or transporters on the BBB, facilitate the crossing of the barrier via receptor-mediated endocytosis or adsorptive-mediated transcytosis. This strategy enhances therapeutic agents' bioavailability and cellular uptake, offering a potential solution to overcome current limitations in AD treatment. Using nanotechnology to design ligand-conjugated NPs for targeted and sustained drug delivery could significantly improve therapeutic outcomes for AD patients by addressing key pathological processes in the brain.},
}

@article {pmid41391505,
year = {2025},
author = {Liu, Y and Zhang, J and Li, W and Qu, Q and Shan, Z and Liu, C and Jiao, K and Hou, X},
title = {Osthole Ameliorates Cognitive Impairment in Ovariectomized Rats via Estrogen-Mediated Enhancement of Cholinergic Function and Regulation of Neurotransmitter Homeostasis.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110806},
doi = {10.1016/j.neuropharm.2025.110806},
pmid = {41391505},
issn = {1873-7064},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction that is closely associated with cholinergic system damage. Estrogen deficiency is a well-established risk factor for AD in women. Osthole (OST), a phytoestrogen with mild, bidirectional regulatory properties, has been proposed as a potential estrogen replacement. This study aimed to investigate the mechanisms by which OST ameliorates cognitive impairment. Cognitive deficits were induced in female Sprague-Dawley rats by bilateral ovariectomy (OVX), and OST was subsequently administered by oral gavage. Behavioral tests revealed that OST significantly improved learning and memory and reduced anxiety-like and depression-like behaviors in OVX rats. H&E staining and Nissl staining demonstrated that OST reversed neuronal damage in the hippocampus and cortex. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment restored the estrogen-cholinergic-NGF axis: E2, ERα, and ERβ expression were upregulated; Ach, ChAT, NGF, and TrkA levels were increased, whereas AChE activity was decreased. Moreover, OST inhibited neuronal apoptosis by elevating Bcl-2 and reducing Bax expression, enhanced the expression of markers of synaptic plasticity (PSD95, SYN, and BDNF), and modulated neurotransmitter release (GABA and E). Collectively, these multi-target effects identify OST as a promising candidate for treating AD in women.},
}

@article {pmid41390238,
year = {2025},
author = {Mummery, CJ and Rasmussen, J and Blackburn, D and Coulthard, E and Davies, RR and Dorsey, R and Fox, NC and Hosseini, AA and Ivenso, C and Jones, M and Kennelly, SP and Kipps, C and Lashley, D and Mackay, G and Negi, R and Nilforooshan, R and Passmore, PA and Perry, R and Raymont, V and Rowe, JB and Russ, TC and Taylor, JP and Burns, A},
title = {Lecanemab appropriate use recommendations for clinical practice in the UK.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2025-336597},
pmid = {41390238},
issn = {1468-330X},
abstract = {Lecanemab is an anti-amyloid monoclonal antibody, recently approved in the UK as a treatment for mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease (AD) in adults who are apolipoprotein E ε4 gene (APOE4) heterozygotes or non-carriers.A group of UK neurologists, old age psychiatrists and geriatricians with expertise in AD convened to agree appropriate use recommendations for lecanemab in UK clinical practice. The primary focus of these recommendations is safety.Eligibility criteria for lecanemab in the UK include (a) a clinical diagnosis of MCI or mild dementia due to AD, (b) the presence of amyloid-β pathology, confirmed using approved methods (ie, an amyloid positron emission tomography scan or cerebrospinal fluid assay) and (c) APOE4 heterozygous or non-carrier status. Eligibility screening should be conducted in secondary care and those identified as being potentially eligible for lecanemab should be referred to a specialist centre for confirmation of the likely pathological diagnosis, APOE4 counselling and testing and a multidisciplinary consensus decision regarding treatment eligibility. Lecanemab is administered as an intravenous infusion every 2 weeks, and those eligible for treatment should have brain magnetic resonance imaging (MRI) scans prior to the 1st, 5th, 7th and 14th infusions. Specific guidance is provided for safety monitoring and management of potential adverse reactions, including amyloid-related imaging abnormalities and infusion-related reactions.The introduction of lecanemab into UK clinical practice provides an important opportunity to improve services for all people living with dementia, not just those eligible for lecanemab treatment.},
}

@article {pmid41390089,
year = {2025},
author = {Sheng, J and Wang, L and Zhang, Q and Chien Chou, JT and Zhang, R and Li, T and Lu, Y},
title = {Integrating multimodal data to identify single nucleotide polymorphism-related biomarkers and regulatory mechanisms in Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.12.022},
pmid = {41390089},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease with unclear regulatory mechanisms at the cell-type level. A multi-omics model called single nucleotide polymorphisms (SNPs)-transcriptomic-single-nucleus ribonucleic acid sequencing (snRNA-seq) integration (STSNI) is proposed to identify SNPs-related biomarkers and regulatory mechanisms in AD. Differential expression analysis identified differentially expressed genes (DEGs) between AD patients and healthy controls (HCs) in the GSE118553 dataset. Cell-type annotation in the GSE138852 dataset revealed several cell subclusters, and DEGs were identified within these subclusters. Intersection analysis among DEGs from the GSE118553 dataset, cell-subcluster-specific DEGs from the GSE138852 dataset, and SNP-associated genes from the ADNI2 dataset yielded 14 overlapping genes. Using the least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) algorithms, six biomarkers were identified. Functional enrichment and gene set enrichment analysis (GSEA) linked these biomarkers to pathways such as carboxylic acid catabolic process, exocytic vesicle membrane, and carbon metabolism. Meanwhile, six cell types were identified, including astrocytes, endothelial cells, oligodendrocytes, oligodendrocyte progenitor cells (OPCs), microglia, and neurons. The biomarker-transcription factor (TF) network indicated that Cispb M4676 regulates IQGAP2, NRXN1, GRIA3 and FGF14. Overall, our study identified six SNP-related biomarkers (IQGAP2, HHAT, FGF14, CTNNA3, GRIA3, and NRXN1) associated with AD. The STSNI framework provided novel insights into the cellular and molecular mechanisms underlying AD. Significance Statement: As the global population continues to age, Alzheimer's disease (AD) has emerged as a major public health concern. The pathological changes associated with AD include the formation of extracellular amyloid plaques, intracellular neurofibrillary tangles, and neuronal loss with gliosis proliferation. Bioinformatics methods are used to explore the immune infiltration characteristics, biological pathways and regulatory mechanisms of single nucleotide polymorphisms (SNPs) related key genes in AD. The pathogenesis of AD from the overall level and single-cell level is explored based on SNPs-related genes, combined with snRNA-seq data and transcriptome data. This study provides an opportunity for the discovery of novel diagnostic molecular markers and potential treatment targets to serve as the foundation for the development of more effective management techniques for AD.},
}

@article {pmid41389844,
year = {2025},
author = {Shi, H and Zhao, Y},
title = {Astaxanthin inhibits the aggregation and cytotoxicity of tau4RDΔK280 via possible interaction with the aggregation-prone segments.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106103},
doi = {10.1016/j.neuint.2025.106103},
pmid = {41389844},
issn = {1872-9754},
abstract = {Tauopathies are a group of neurodegenerative disorders characterized by the presence of abnormal aggregates of microtubule associated protein tau in the brain. In the most common tauopathy, Alzheimer's disease (AD), the aggregation of tau is closely linked with synaptic dysfunction and neuronal death, while targeting the aggregation of tau has been demonstrated to have therapeutic potential. Astaxanthin is a carotenoid with neuroprotective function, which has been shown to inhibit Aβ-induced pathology in AD animal and cell models. However, the effects of astaxanthin on tau aggregation and toxicity are much less explored. In this study, we generated a cell model of tauopathy overexpressing the amyloidogenic pro-aggregant tau repeat domains carrying the FTDP-17 mutation ΔK280 in N2a cells (N2a-tau4RDΔK280). It was found that astaxanthin treatment alleviated the cytotoxicity of N2a-tau4RDΔK280 cells while reducing the amount of tau4RDΔK280 aggregates in the cells. Results from the thioflavin T aggregation assay demonstrated that astaxanthin inhibited the aggregation of tau4RDΔK280 in vitro. Further analyses with transmission electron microscopy confirmed that astaxanthin reduced the formation of amyloid fibril structures of tau4RDΔK280 in vitro. Thus, astaxanthin might inhibit the cytotoxicity of N2a-tau4RDΔK280 cells by preventing the formation of tau4RDΔK280 aggregates. Molecular docking simulation analyses revealed that astaxanthin was able to directly interact with tau4RDΔK280 as well as several key aggregation-prone segments of tau protein. In conclusion, our results demonstrated that astaxanthin might exert neuroprotection by inhibiting the formation of tau aggregates via direct interaction with the key aggregation-prone segments.},
}

@article {pmid41389629,
year = {2025},
author = {Ruiz de Martín Esteban, S and Grande, MT and Martínez-Relimpio, AM and Herráez-Aguilar, D and Mostany, R and Hillard, CJ and Hind, WH and Romero, J},
title = {Treatment with a botanical mixture of cannabidiol:Δ[9]-tetrahydrocannabinol enhances microglial phagocytosis and shapes amyloid plaques in a mouse model of Alzheimer's disease.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {194},
number = {},
pages = {118902},
doi = {10.1016/j.biopha.2025.118902},
pmid = {41389629},
issn = {1950-6007},
abstract = {The potential use of phytocannabinoids in neurodegenerative disorders is currently under intense investigation based on their potential anti-inflammatory, antioxidant, and neuroprotective effects. Here, we tested the effects of chronic (28 days) treatment with a complex botanical mixture of purified cannabidiol:Δ[9]-tetrahydrocannabinol (CBD:THC, 99:1) in male 5xFAD mice, a murine model of Alzheimer's disease that recapitulates amyloid pathology. Effects of exposure to this cannabinoid mixture were evaluated using behavioral tests (elevated plus maze for anxiety, tail suspension for depression-like behavior, rotarod for motor coordination, open field for locomotor activity, and novel object recognition for memory), quantification of protein expression (IL-1β, CD40, TREM2, COX2), assessment of functional parameters (microglial phagocytic activity by flow cytometry), and in vivo multiphoton microscopy (time-course of changes of neuritic plaque structural features). Twice daily dosing with 50 mg/kg subcutaneously (s.c.) significantly reduced locomotion, increased anxiety- and depression-like behaviors and had no effect on memory and motor coordination. In vivo imaging experiments suggest that the CBD:THC treatment enhanced microglial phagocytic activity on amyloid plaques; this effect was observed both in plaque features (multiphoton microscopy measurements) as well as in microglia (flow cytometry data). Exposure to CBD:THC induced significant changes in in vivo microglia-amyloid interactions, increasing phagocytic activity and reducing the amyloid peptide accumulation in the neuritic plaques. Thus, CBD:THC (99:1) may be a promising treatment to reduce amyloid pathology, though caution should be noted due to the behavioral alterations observed, i.e., increased anxiety- and depression-like behaviors as well as decreased locomotion.},
}

@article {pmid41389410,
year = {2025},
author = {Li, X and Yan, S and Li, M and Liu, R and Lu, Q and Lu, M and Bai, F and Shen, QD},
title = {Piezoelectric nanoparticle-driven rhythmic ultrasound neuromodulation for treatment of early-stage Alzheimer's disease.},
journal = {Biomaterials},
volume = {328},
number = {},
pages = {123905},
doi = {10.1016/j.biomaterials.2025.123905},
pmid = {41389410},
issn = {1878-5905},
abstract = {Synaptic dysfunction and loss are central drivers of cognitive decline in Alzheimer's disease (AD), yet current therapeutic approaches targeting amyloid-β or tau pathology have largely failed to rescue synaptic function. Neural oscillations and synaptic plasticity are tightly coupled and underpin functional brain networks, suggesting that modulating oscillatory dynamics may offer new therapeutic avenues. Here, we developed a strategy for precise, non-genetic neuromodulation using focused ultrasound and piezoelectric Ba0.85Ca0.15Zr0.1Ti0.9O3 (BCZT) nanoparticles to generate targeted, gamma-frequency electromagnetic fields in the hippocampal CA3 subregion of early-stage AD mouse models. This rhythmic stimulation effectively restored impaired gamma oscillations, enhanced synaptic plasticity, and remodeled memory-related network connectivity, as validated by local field potential recordings, patch-clamp electrophysiology, and functional MRI. Mechanistically, we demonstrate that NF-κB transcription factor activation during rhythmic stimulation regulates AMPAR trafficking by balancing synaptic internalization and delivery, with concurrent upregulation of P300-mediated histone acetylation. Our findings establish a novel paradigm for spatially precise, periodic neuromodulation that restores hippocampal information processing and network function in early AD, highlighting the therapeutic potential of piezoelectric nanomaterials for neural circuit repair in AD and other neurodegenerative diseases characterized by impaired neural rhythms.},
}

@article {pmid41389269,
year = {2025},
author = {Isaković, J and Athanassiadis, A and Khubeis, M},
title = {Stem cells strike back: advancements in Alzheimer's and Parkinson's disease treatment and modeling efforts from 2019 to 2024.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {104},
number = {1},
pages = {2},
pmid = {41389269},
issn = {1432-1440},
mesh = {Humans ; *Alzheimer Disease/therapy ; *Parkinson Disease/therapy ; *Stem Cell Transplantation/methods ; Animals ; Clinical Trials as Topic ; *Stem Cells/cytology/metabolism ; Cell Differentiation ; },
abstract = {This review critically evaluates the current state of stem cell therapy (SCT) for treating and modeling of Alzheimer's (AD) and Parkinson's disease (PD). It includes an in-depth analysis of both preclinical and clinical studies, with a particular focus on clinical trials conducted between 2019 and 2024, reflecting recent advancements in the field. Preclinical studies were examined to elucidate the molecular mechanisms underlying SCT and identify developments that could be translated into clinical practice. Within these studies, stem cells, including embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs), have shown high differentiation and proliferation abilities. These properties, along with their capacity to inhibit inflammation, prevent apoptosis, and stimulate angiogenesis, make them promising candidates for treating AD and PD. Over the past 15 years, 76 SCT-based trials have been conducted-27 for AD and 48 for PD-with more than half occurring in the past 5 years. Despite the promise of SCT, the field faces challenges such as ethical concerns regarding the use of ESCs, heterogeneity of isolated cultures, and inconsistent results across preclinical trials. Novel materials and electromagnetic fields (EMFs) offer potential solutions to these issues. While bioengineering approaches can enhance the successful engraftment of transplanted stem cells, EMFs can direct the cells' migration and differentiation. In conclusion, although significant progress has been made in SCT, ongoing efforts are needed to address existing challenges. Nevertheless, SCT holds considerable promise for the future, offering potential breakthroughs in the treatment of neurodegenerative diseases.},
}

Humans
*Alzheimer Disease/therapy
*Parkinson Disease/therapy
*Stem Cell Transplantation/methods
Animals
Clinical Trials as Topic
*Stem Cells/cytology/metabolism
Cell Differentiation

@article {pmid41388533,
year = {2025},
author = {Khan, AR and Makhoul, GW and Raji, MA},
title = {Mirtazapine for gastrointestinal side effects of glucagon-like peptide-1 receptor agonist therapy in older adults.},
journal = {Endocrine regulations},
volume = {59},
number = {1},
pages = {260-264},
doi = {10.2478/enr-2025-0030},
pmid = {41388533},
issn = {1336-0329},
mesh = {Humans ; Aged ; Female ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Diabetes Mellitus, Type 2/drug therapy ; *Mirtazapine/therapeutic use ; *Hypoglycemic Agents/adverse effects ; Glucagon-Like Peptides/adverse effects ; *Gastrointestinal Diseases/chemically induced/drug therapy ; Nausea/chemically induced/drug therapy ; Vomiting/chemically induced/drug therapy ; Glucagon-Like Peptide 1 ; },
abstract = {Objective. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) play a role in management of type 2 diabetes (T2D) and obesity by promoting glycemic control and weight reduction. Beyond these benefits, GLP-1 RAs have demonstrated positive effects on cardiovascular, renal, and neurological health, with emerging evidence supporting their therapeutic potential in conditions such as chronic kidney disease, asthma, obstructive sleep apnea, Parkinson's disease, and Alzheimer's disease. However, their widespread clinical use is often hindered by gastrointestinal side effects including nausea, anorexia, vomiting, and diarrhea that limit adherence and dose titration. Effective management of these adverse effects is essential to optimize treatment outcomes and maintain long-term therapy. Case report. A 72-year-old woman with a history of cognitive impairment, T2D, atrial fibrillation, obesity, and mood disorders presented with persistent gastrointestinal symptoms while receiving semaglutide. Dose escalation was restricted due to severe nausea, vomiting, and diarrhea, which markedly affected her quality of life. To manage these symptoms, mirtazapine was initiated. Following its introduction, the patient reported significant improvement in gastrointestinal tolerance enabling continued semaglutide therapy and successful dose advancement. Additional benefits included enhanced mood, better sleep, and overall well-being. No adverse effects related to mirtazapine were observed throughout the treatment. Conclusion. This case suggests that mirtazapine may be beneficial in mitigating GLP-1 RA-induced gastrointestinal side effects, thereby improving adherence and therapeutic efficacy. Further research is needed to evaluate the safety, mechanism, and generalizability of this approach in broader clinical practice.},
}

Humans
Aged
Female
*Glucagon-Like Peptide-1 Receptor Agonists
*Diabetes Mellitus, Type 2/drug therapy
*Mirtazapine/therapeutic use
*Hypoglycemic Agents/adverse effects
Glucagon-Like Peptides/adverse effects
*Gastrointestinal Diseases/chemically induced/drug therapy
Nausea/chemically induced/drug therapy
Vomiting/chemically induced/drug therapy
Glucagon-Like Peptide 1

@article {pmid41388352,
year = {2025},
author = {Akinluyi, ET and Takahashi-Yamashiro, K and Connolly, MG and Poon, WW and Macauley, MS},
title = {Interplay between CD33 and TREM2 in Alzheimer's Disease: Potential Mechanistic Insights into Microglial Function in Amyloid Pathology.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00805},
pmid = {41388352},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques, tau neurofibrillary tangles, and progressive neuronal loss leading to cognitive decline. With millions affected worldwide, there remains an urgent need for innovative treatment strategies to combat this disease. Genome-wide association studies (GWAS) have identified genes expressed in microglia, the resident immune cells of the brain, as key mediators of AD susceptibility. Among microglial risk genes, CD33 and TREM2 stand out for their contrasting roles in AD risk. Accumulating evidence indicates that these receptors converge on overlapping signaling pathways to regulate microglial activation and Aβ clearance. Here, we review the current understanding of CD33 and TREM2 biology in AD, with a focus on their potential crosstalk and functional antagonism. We propose potential mechanistic models by which human CD33 isoforms regulate TREM2 activity in either the absence or presence of Aβ pathology and discuss therapeutic strategies targeting this axis. Together, these insights suggest new avenues for microglia-targeted interventions in AD.},
}

@article {pmid41387197,
year = {2025},
author = {Fredriksen-Goldsen, KI and Teri, L and Kim, HJ and Jones-Cobb, B and LaFazia, D and McKenzie, G and Petros, R and Jung, H and Oswald, AG and Hoy-Ellis, C and Emlet, C},
title = {Innovations in Dementia Empowerment and Action: RCT for Underserved Communities.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70189},
pmid = {41387197},
issn = {1532-5415},
support = {R01AG055488//National Institute on Aging of the National Institutes of Health/ ; },
abstract = {BACKGROUND: Research has revealed dementia disparities among underserved older adults. Built upon standard-Reducing Disability in Alzheimer's Disease (s-RDAD), Innovations in Dementia Empowerment and Action (IDEA) is designed and culturally tailored for underserved communities through an empowerment stigma-reduction cognitive-behavioral intervention and tested with sexual and gender minority (SGM) adults and care partners.

METHODS: The study is a 2-arm (IDEA and s-RDAD), single-blind, randomized controlled trial (RCT) with a staggered multiple baseline design. With 161 dyads (person living with dementia/care partner), the aim of the study is to compare the two arms via between and within group differences on primary (physical activity) and secondary outcomes (e.g., quality of life, physical functioning, and resource literacy) at post-treatment, and 30 and 56 week follow-up.

RESULTS: When comparing the two arm between-group differences, the IDEA care partners' community resource literacy was significantly higher at 30-week follow-up than for s-RDAD (contrast = 0.10, p = 0.005). While both intervention arms demonstrated efficacy with significant improvement in physical activity (contrastIDEA = 0.10, p = 0.010; contrasts-RDAD = 0.14, p < 0.001) and quality of life (contrastIDEA = 0.06, p < 0.001; contrasts-RDAD = 0.03, p = 0.035) for the person with dementia at post-treatment, positive treatment effects on physical activity (contrastIDEA = 0.09, p = 0.032) and quality of life (contrastIDEA = 0.03, p = 0.040) persisted at 30 weeks for IDEA but not for s-RDAD.

CONCLUSION: While both intervention arms were efficacious, IDEA demonstrated sustained efficacy. The cultural tailoring of interventions is promising to address disparities in dementia care and interventions in underserved communities. Future research is needed for the translation of this efficacious intervention to the larger community.

CLINICALTRIALS: gov identifier: NCT03550131.},
}

@article {pmid41385058,
year = {2025},
author = {Jiang, H and Escamilla, S and Beestrum, M and Salas-Lucia, F},
title = {Cost-effectiveness of testing biofluid biomarkers to diagnose Alzheimer's disease: a systematic review.},
journal = {The European journal of health economics : HEPAC : health economics in prevention and care},
volume = {},
number = {},
pages = {},
pmid = {41385058},
issn = {1618-7601},
abstract = {BACKGROUND: Alzheimer's disease (AD) affects tens of millions of individuals and their families in the world. As AD progresses, the effectiveness of treatment declines, making a timely diagnosis crucial. One promising approach for timely diagnosis is testing biofluid biomarkers in patients' blood and cerebrospinal fluid (CSF). However, a comprehensive evaluation of whether these tests are cost-effective is missing. Here, we conducted a systematic review to assess the cost-effectiveness of testing biofluid biomarkers to diagnose AD.

METHOD: We searched PubMed, Embase, Cochrane Library, and Web of Science for studies published until October 2024. Studies were included if published in English, conducted an economic evaluation of CSF or blood biomarker testing to diagnose AD, and provided economic outcomes. We assessed the quality of studies using the CHEERS 2022 criteria.

RESULTS: Nine studies were included: six evaluated CSF biomarker tests and three on blood biomarker tests. All studies used model-based simulations (decision trees or Markov models) rather than trial-based evaluations. CSF biomarker tests were mostly cost-effective compared to neurocognitive assessments or neuroimaging, while blood biomarker tests showed mixed results. Key cost-effectiveness contributors included AD prevalence, diagnostic accuracy, and treatment effectiveness. Studies met ~ 80% of the CHEERS criteria, with missing information on patient engagement.

CONCLUSION: Our review supports that biofluid biomarker testing could be cost-effective to diagnose AD. Given the lack of trial-based economic evaluations, model-based studies are a valuable starting point. Future evaluations should incorporate patient-centered outcomes and consider the emotional value and other socio-economic factors that affect patients and families suffering from AD.},
}

@article {pmid41384832,
year = {2025},
author = {Villarejo Galende, A and González-Sánchez, M and Hilario, A and Llamas-Velasco, S and Morenas-Rodríguez, E and Muñoz-García, MI and Ramos-González, A and Pérez-Martínez, DA and Blanco-Palmero, VA},
title = {Severe symptomatic amyloid-related imaging abnormalities in Alzheimer's disease: Two case reports and systematic review of reported cases.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251404505},
doi = {10.1177/13872877251404505},
pmid = {41384832},
issn = {1875-8908},
abstract = {BackgroundAmyloid-related imaging abnormalities (ARIA) are a recognized complication of anti-amyloid monoclonal antibodies for Alzheimer's disease (AD). While typically asymptomatic, a subset of patients develops severe clinical symptoms and radiological findings requiring intensive management. Data on their presentation, treatment, and outcomes remain limited.ObjectiveWe report two cases and analyze the clinical features of all published cases of severe symptomatic ARIA, with a focus on associated risk factors, therapeutic approaches, and patient outcomes.MethodsWe report two cases of severe symptomatic ARIA in patients treated with gantenerumab. A systematic review was conducted following PRISMA guidelines using MEDLINE, Web of Science, and manual reference screening. We included case reports and series providing individual-level data on symptomatic ARIA episodes classified as severe by clinical criteria. Demographic, genetic, clinical, radiological, therapeutic, and outcome data were extracted.ResultsThirty-six cases were included (2 new and 34 from 21 publications). Fifteen cases were associated with lecanemab, 10 with gantenerumab, 6 with donanemab, and 5 with other antibodies. APOE ε4 was present in 62.5%, including 10 ε4/ε4 homozygotes. Baseline MRI showed hemorrhagic markers in 10 cases, including superficial siderosis in 2 of the 5 patients with isolated macrohemorrhages. Most episodes occurred within 6 months of treatment. Symptoms included altered consciousness (75%), focal deficits (66.7%), seizures (38.9%), and headache (36.1%). ARIA-E resolved in all non-fatal cases. Corticosteroids were used in 72%. Among the patients whose outcome data were available, 15 patients recovered completely, 10 had persistent deficits, and 10 died.ConclusionsSevere symptomatic ARIA is a rare but serious adverse effect of anti-amyloid therapy. Standardized diagnostic and therapeutic guidelines are needed to minimize ARIA-related morbidity and mortality.PROSPERO registration no. CRD420251055067.},
}

@article {pmid41383948,
year = {2025},
author = {Mu, L and Wang, Y},
title = {The role of gut microbiota-derived metabolites in neuroinflammation.},
journal = {Neuroprotection (Chichester, England)},
volume = {3},
number = {2},
pages = {131-144},
pmid = {41383948},
issn = {2770-730X},
abstract = {Neuroinflammation, a key defense mechanism of the nervous system, is associated with changes in inflammatory markers and stimulation of neuroimmune cells such as microglia and astrocytes. Growing evidence indicates that the gut microbiota and its metabolites directly or indirectly regulate host health. According to recent studies, bacterial dysbiosis in the gut is closely linked to several central nervous system disorders that cause neuroinflammation, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, sepsis-associated encephalopathy, and ischemic stroke. Recent findings indicate a bidirectional communication network between the gut microbiota and central nervous system that influences neuroinflammation and cognitive function. Dysregulation of this system can affect the generation of cytotoxic metabolites, promote neuroinflammation, and impair cognition. This review explores the lesser-studied microbiota-derived metabolites involved in neuroinflammation-bile acids, trimethylamine-N-oxide, and indole derivatives-as targets for creating new treatment tools for neuroinflammatory illnesses, as well as possible biomarkers for early diagnosis and prognosis.},
}

@article {pmid41383947,
year = {2025},
author = {Schwartz, SS and Rhea, EM and Banks, WA and Herman, ME},
title = {Beta cells to brain cells: The pivotal role of insulin and glucose metabolism in Alzheimer's disease.},
journal = {Neuroprotection (Chichester, England)},
volume = {3},
number = {2},
pages = {145-164},
pmid = {41383947},
issn = {2770-730X},
abstract = {The risk factors and neuropathologies of cognitive decline and the onset and progression of dementia-related disorders were, until recently, obtuse. A critical predisposing factor to Alzheimer's disease (AD) that has emerged is glucose dysmetabolism. It is now understood that energy imbalances or excess nutrient intake sit in the crosshairs of neurodegeneration. Within the brain, the regulation of glucose operates semiautonomously from the periphery to ensure a defended, uninterrupted supply of glucose for neuronal processes. In this localized brain energetic milieu, hyperglycemia, hyperinsulinemia, and insulin resistance constitute independent risk factors for AD. Disturbances in the blood‒brain barrier (BBB) and brain insulin resistance are two newly understood insults connecting glucose metabolism with AD. This dysglycemia waylays insulin signaling, an otherwise potentially protective mechanism against AD plaques. In parallel, studies in the clinical setting demonstrate that glucose-lowering in patients with type 2 diabetes (T2D) reduces the risk of AD. The American Diabetes Association (ADA) elevated its guidelines to include cognitive issues (or risk) as a comorbidity in T2D patient treatment plans. Choice of antidiabetes therapy is imperative: evidence supports the use of metformin, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide-1 receptor analogs, and sodium glucose cotransporter 2 inhibitors to help prevent and mitigate cognitive outcomes and AD. Sulfonylureas, on the other hand, may actually worsen cognitive deficits and integrity. We are at a fascinating juncture: preclinical research is at a stage to inform the development of rational previously unexplored targets. Simultaneously, current clinical evidence is translatable now into real-world strategies to reduce the incidence and severity of comorbid AD in our aging population.},
}

@article {pmid41383815,
year = {2025},
author = {Zhang, R and Liu, YY and Xia, X and Li, X},
title = {Unvalidated efficacy and significant risks hinder clinical use of deep cervical lymphatic-venous anastomosis for Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1671741},
pmid = {41383815},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and the pathological accumulation of amyloid-beta (Aβ) plaques and tau tangles. Recent studies suggest that dysfunction of the cerebral lymphatic clearance system may contribute to the progression of AD. This review critically examines the potential of deep cervical lymphatic-venous anastomosis (LVA) as a treatment for enhancing brain protein clearance and reducing cognitive decline in AD patients. Although animal models indicate that improving lymphatic drainage could facilitate Aβ clearance, clinical evidence is still insufficient. Current studies often have small sample sizes, short follow-up periods, and methodological weaknesses. Despite preliminary reports of cognitive improvements in small-scale clinical trials, the efficacy of LVA remains unproven, making widespread clinical adoption premature. Ethical concerns and technical challenges also pose significant barriers to clinical implementation. Rigorous randomized controlled trials (RCTs) are necessary to assess the long-term safety and efficacy of LVA for treating AD. Furthermore, the establishment of clear ethical and regulatory frameworks is essential before clinical use.},
}

@article {pmid41383524,
year = {2025},
author = {Zhang, X and Zhong, M and Li, Y and Wang, H and Xi, G and Wang, F and Cheng, C and Shi, Y},
title = {Oral microbiota and central nervous system diseases: A review.},
journal = {Neuroprotection (Chichester, England)},
volume = {3},
number = {1},
pages = {79-94},
pmid = {41383524},
issn = {2770-730X},
abstract = {Oral microbiota is the second largest microbial colony in the body and forms a complex ecological community that influences oral and brain health. Impaired homeostasis of the oral microbiota can lead to pathological changes, resulting in central nervous system (CNS) diseases. However, the mechanisms and clinical value of how the oral microbiome influences the brain remain unclear. This review summarizes recent clinical findings on the role of the oral microbiota in CNS diseases and proposes potential approaches to understand the way the oral microbiota and brain communicate. We propose three underlying patterns involving neuroinflammation, neuroendocrine regulation, and CNS signaling between oral microbiota and CNS diseases. We also summarize the clinical characteristics and potential utilization of the oral microbiota in ischemic stroke, Alzheimer's and Parkinson's disease, intracranial aneurysms, and mental disorders. Although the current findings are preliminary and clinical evidence is incomplete, oral microbiota is a potential biomarker for the clinical diagnosis and treatment of CNS diseases.},
}

@article {pmid41383520,
year = {2025},
author = {Saxena, SK and Sharma, D and Kumar, S and Maurya, VK and Ansari, S and Malhotra, HS and Singh, A},
title = {Decoding the role of large heat shock proteins in the progression of neuroinflammation-mediated neurodegenerative disorders.},
journal = {Neuroprotection (Chichester, England)},
volume = {3},
number = {1},
pages = {48-62},
pmid = {41383520},
issn = {2770-730X},
abstract = {Chronic neuroinflammation and protein aggregation are the fundamental events mainly responsible for the progression of neurodegenerative diseases (NDs). Potential neurotoxic changes in the intra- and extracellular environment are typical hallmarks of many NDs. Treatment of ND is challenging, as the symptoms in these patients arises when a significant numbers of neurons have already been destroyed. Heat shock proteins (HSPs) can bind to recipient cells that are susceptible to stress, such as neurons, in the extracellular environment, therefore enhancing stress resistance. Among all, HSP60, HSP70, and HSP90 are highly conserved molecular chaperones involved in protein folding and assembly, maintaining cellular homeostasis in the central nervous system. Notably, α-synuclein accumulation is a major pathophysiology in Parkinson's disease, where HSP90 modulates the assembly of α-synuclein in vesicles to prevent its accumulation. Moreover, HSP90 regulates the activity of the glycogen synthase kinase-3β protein, which is crucial in diabetes mellitus-associated neurocognitive disorder. Therefore, understanding the molecular mechanism by which HSPs facilitate protein aggregation and respond to inflammatory stimuli, including metabolic disease such as diabetes, is essential for understanding the significance of HSPs in NDs. This review emphasizes the role of various HSPs in the progression of NDs such as Alzheimer's, Parkinson's, multiple sclerosis, and Huntington's disease, including diabetes, which is one of the major risk factors for neurodegeneration.},
}

@article {pmid41383377,
year = {2024},
author = {Hanumanthappa, R and Parthasarathy, A and Heggannavar, GB and Pc, K and Nanjaiah, H and Kumbhar, R and Devaraju, KS},
title = {Recent advances in therapeutic strategies for Alzheimer's and Parkinson's disease using protein/peptide co-modified polymer nanoparticles.},
journal = {Neuroprotection (Chichester, England)},
volume = {2},
number = {4},
pages = {255-275},
pmid = {41383377},
issn = {2770-730X},
abstract = {The blood-brain barrier (BBB), which protects the brain from foreign molecules, makes delivery of drugs to the central nervous system is challenging. Nanoparticles (NPs) have been used over the past decade as drug delivery systems for the treatment of many disorders with great results. However, the effectiveness of NPs in delivering drugs to the brain for the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD) is limited by the BBB. A recent breakthrough in nanotechnology delivery systems involves the use of surface-modified polymer NPs that enhance drug absorption and transport across the BBB; however, the technology still has some limitations. Studies conducted over the past few years have demonstrated that NPs modified with peptides or proteins can effectively cross the BBB via specific receptors, thus enhancing their delivery efficiency. In this review, we explore the use of polymer NPs combined with peptides and proteins for the treatment of AD and PD. This discussion focuses on the pathophysiology of these diseases, the BBB, and the potential of therapeutics based on co-modifying NPs with peptides and proteins. Additionally, we outline future directions for the use of polymer NPs conjugated with these biomolecules.},
}

@article {pmid41382294,
year = {2025},
author = {Su, X and Takayanagi, R and Maeda, H and Saido, TC and Ohshima, T},
title = {Sex-related upregulation of bone morphogenetic protein signaling inhibits adult neurogenesis in APP[NL-G-F] alzheimer's disease model mice.},
journal = {Biology of sex differences},
volume = {16},
number = {1},
pages = {103},
pmid = {41382294},
issn = {2042-6410},
support = {JP22K06464//Japan Society for the Promotion of Science/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; *Neurogenesis/physiology ; Female ; Male ; Up-Regulation ; Mice, Transgenic ; Disease Models, Animal ; Signal Transduction ; Mice, Inbred C57BL ; *Bone Morphogenetic Proteins/metabolism ; *Sex Characteristics ; Hippocampus/metabolism ; Mice ; Neural Stem Cells ; Estrogens/pharmacology ; },
abstract = {BACKGROUND: Bone morphogenetic proteins (BMPs) have been reported in many studies to be related to adult neurogenesis. Neurogenic impairment is a hallmark of Alzheimer's disease (AD), while the involvement of BMPs remains unclear.

METHODS: AD models were established using APP[NL-G-F] transgenic mice and C57BL/6 mice subjected to intracerebral injection of Aβ(25-35) peptide. Female APP[NL-G-F] mice received pharmacological inhibitor treatment, whereas Neuro2a cells were exposed to estrogen stimulation in vitro. Immunofluorescence staining was conducted to evaluate hippocampal neural stem cell proliferation. The hippocampus and cellular pellets were isolated, and quantitative PCR (qPCR) was employed to determine mRNA expression levels.

RESULTS: Our study revealed that APP[NL-G-F] mice and Aβ-injected mice exhibited impaired neurogenesis in the brain, with a clear sex-dependent difference only in APP mice. Several BMPs were markedly upregulated in the hippocampus of AD model mice, with significantly higher expression in females than in males. BMP inhibitor attenuated neural stem cell proliferation deficits in female APP[NL-G-F] mice. Estrogen stimulation robustly enhanced BMP6 expression in Neuro2a cells.

CONCLUSIONS: Our findings reveal a sex-dependent impairment of neurogenesis in APP[NL-G-F] mice driven by BMP signaling. Blocking BMP signaling enhances adult neural stem cell proliferation in female APP[NL-G-F] mice, providing a potential therapeutic target for AD.},
}

Animals
*Alzheimer Disease/metabolism/physiopathology
*Neurogenesis/physiology
Female
Male
Up-Regulation
Mice, Transgenic
Disease Models, Animal
Signal Transduction
Mice, Inbred C57BL
*Bone Morphogenetic Proteins/metabolism
*Sex Characteristics
Hippocampus/metabolism
Mice
Neural Stem Cells
Estrogens/pharmacology

@article {pmid41382170,
year = {2025},
author = {Jannati, A and Thompson, K and Toro-Serey, C and Gomes-Osman, J and Banks, RE and Higgins, C and Showalter, J and Bates, D and Tobyne, S and Pascual-Leone, A},
title = {Concurrent detection of cognitive impairment and amyloid positivity with a multimodal machine learning-enabled digital cognitive assessment.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {261},
pmid = {41382170},
issn = {1758-9193},
mesh = {Humans ; *Machine Learning ; *Cognitive Dysfunction/diagnosis/metabolism ; *Amyloid beta-Peptides/metabolism ; Male ; Female ; Aged ; Neuropsychological Tests ; *Alzheimer Disease/diagnosis ; Biomarkers/blood ; Aged, 80 and over ; tau Proteins/metabolism ; Brain/metabolism/diagnostic imaging ; Middle Aged ; },
abstract = {BACKGROUND: Early identification of cognitive impairment and brain pathology associated with Alzheimer's disease (AD) is essential to maximize benefits from lifestyle interventions and emerging pharmacologic disease-modifying treatments (DMT). Digital cognitive assessments (DCAs) can quickly capture an array of metrics that can be used to train machine-learning (ML) models to concurrently evaluate different outcomes. DCAs have the potential to optimize clinical workflows and enable efficient assessment of cognitive function and the likelihood of a given underlying pathology.

METHODS: We assessed the ability of a multimodal ML-enabled DCA, the Digital Clock and Recall (DCR), to concurrently estimate brain amyloid-beta (Aβ) status and detect cognitive impairment, as compared with traditional cognitive assessments, including the MMSE, RAVLT, a DCA, Cognivue[®], and blood-based biomarkers in 930 participants from the Bio-Hermes-001 clinical study.

RESULTS: Aβ42/40, p-tau181, APS, and p-tau217 poorly classified cognitive impairment (AUCs: 0.61; 0.63; 0.63; 0.70, respectively), but accurately classified Aβ status (AUCs: 0.81; 0.78; 0.85, 0.89, respectively). MMSE, RAVLT, and Cognivue poorly classified Aβ status (AUCs: 0.70, 0.73, 0.70, respectively). However, separate multimodal, DCR-based ML classification models, run in parallel, accurately classified both cognitive impairment (AUC = 0.83) and Aβ-PET status (AUC = 0.81).

CONCLUSIONS: DCAs that leverage digital technologies to generate advanced metrics, such as the DCR, enable accurate and efficient detection of cognitive impairment associated with AD pathology. They have the potential to empower health systems and primary care providers to help their patients make timely treatment decisions.},
}

Humans
*Machine Learning
*Cognitive Dysfunction/diagnosis/metabolism
*Amyloid beta-Peptides/metabolism
Male
Female
Aged
Neuropsychological Tests
*Alzheimer Disease/diagnosis
Biomarkers/blood
Aged, 80 and over
tau Proteins/metabolism
Brain/metabolism/diagnostic imaging
Middle Aged

@article {pmid41381656,
year = {2025},
author = {Riley, S and Nguyen, V and Bhattacharjee, R and Ng, PQ and Ritchie, T and Kamath, KS and Fisk, I and Gecz, J and Kumar, R and Searle, IR},
title = {TMT-based quantitative proteomic assessment of Vicia sativa induced neurotoxicity by β-cyano-L-alanine and γ-glutamyl-β-cyano-L-alanine in SH-SY5Y cells.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-30121-2},
pmid = {41381656},
issn = {2045-2322},
support = {BB/V018108/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; LP200200957//Australian Research Council/ ; LP200200957//Australian Research Council/ ; LP200200957//Australian Research Council/ ; UA720//South Australian Grains and Industry Trust/ ; },
abstract = {β-cyano-L-alanine (BCA) and γ-glutamyl-β-cyano-L-alanine (GBCA) are the primary antinutritional compounds in Vicia sativa, a high-protein, drought-tolerant legume. While their neurotoxicity in monogastric animals has been reported, the molecular basis remains largely unknown. In this study, we optimised a rapid in vitro assay using retinoic acid-differentiated SH-SY5Y human neuroblastoma cells to assess BCA and GBCA toxicity, and then applied Tandem mass tags (TMT)-mass spectrometry (MS)-based quantitative proteomics to identify dysregulated proteins. BCA treatment dysregulated the proteins involved in DNA damage, translation, and oxidative stress, many of which are associated with neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease, as well as various cancers. In contrast, GBCA impacted the proteins linked to mitosis, cell cycle regulation, and apoptosis pathways. Interestingly, the absence of overlapping dysregulated proteins between BCA- and GBCA-treated cells suggested that the two toxins likely induce neurotoxicity via distinct mechanisms. These findings offer new insights into the molecular and cellular alterations caused by V. sativa toxins and their implications for animal feed safety.},
}

@article {pmid41381439,
year = {2025},
author = {Ang, S and Zhang, X and Hong, J and Xue, K and Li, J and Du, X and Gao, Y and Wang, X and Li, X and Chen, B and Li, Y and Zhang, J and Liu, S},
title = {The safety and efficacy of gamma frequency auditory and visual stimulation in the treatment of alzheimer's disease: a systematic review and meta-analysis.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {523},
pmid = {41381439},
issn = {2158-3188},
support = {82271546//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2025-ZZ-004//National Clinical Key Specialty Construction Program - Independent Research Project/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with cognitive decline and significant global health burden. Current treatments offer limited benefits, highlighting the need for novel therapies. Gamma-frequency auditory and visual stimulation (GFAVS), utilizing 40 Hz neuromodulation, has gained attention as a non-invasive treatment for cognitive deficits and underlying pathophysiology in AD.

OBJECTIVE: This systematic review and meta-analysis aimed to assess the safety and efficacy of GFAVS in treating Alzheimer's disease (AD) and mild cognitive impairment (MCI).

METHODS: A comprehensive literature search across multiple databases (PubMed, Cochrane Library, MEDLINE, Web of Science, and Embase) was performed up to November 2025. Controlled trials involving adults (≥50 years) with AD or MCI, using GFAVS, were included. Meta-analyses assessed adverse events, cognitive function, and brain changes.

RESULTS: Eleven studies (341 participants) were included. GFAVS was safe, with no significant increase in overall adverse events (RR = 0.99, P = 0.93; RD = -0.01, P = 0.93). However, GFAVS significantly increased the risk of tinnitus (RR = 6.46, P = 0.08; RD = 0.16, P = 0.01). GFAVS significantly improved structural brain changes (SMD = 1.74, P = 0.02), especially in mixed AD and MCI populations (SMD = 3.05, P < 0.00001). Nevertheless, no significant improvements were observed in cognitive function (SMD = 0.16, 95% CI [-0.36 to 0.68], P = 0.55) or activities of daily living (SMD = 0.53, 95% CI [-1.26 to 2.33], P = 0.56), despite the observed structural brain changes. High heterogeneity was observed.

CONCLUSION: GFAVS appears to be well tolerated and may induce structural brain alterations in individuals with Alzheimer's disease or mild cognitive impairment; however, its impact on cognition or daily functioning remains to be established. Large-scale, rigorously designed trials are required to clarify optimal protocols and address the observed heterogeneity.},
}

@article {pmid41383699,
year = {2024},
author = {Huang, S and Zhang, M},
title = {The role of angiotensin II type 1 receptor pathway in cerebral ischemia‒reperfusion injury: Implications for the neuroprotective effect of ARBs.},
journal = {Neuroprotection (Chichester, England)},
volume = {2},
number = {2},
pages = {100-119},
pmid = {41383699},
issn = {2770-730X},
abstract = {Cerebral ischemia-reperfusion (I/R) injury is a crucial factor that impacts the prognosis of recanalization therapy for acute ischemic stroke (AIS). It has been found that the brain renin-angiotensin system, especially the angiotensin II type 1 receptor (AT1R) pathway, plays a significant role in cerebral I/R injury. This pathway is involved in processes such as oxidative stress, neuroinflammation, apoptosis, and it affects cerebrovascular autoregulation and the maintenance of blood-brain barrier. AT1R blocker (ARB), widely used as an antihypertensive agent, has demonstrated stroke prevention capabilities in numerous prospective studies, independent of its antihypertensive characteristics. Studies focusing on neurological diseases like Alzheimer's disease, Parkinson's disease, and cognitive impairment have confirmed that ARBs exhibit neuroprotective effects and aid in improving neurological functions. Preclinical studies have shown that ARBs can reduce infarct volume and brain edema, inhibit multiple signaling pathways associated with I/R injury, restore energy levels in damaged brain regions, and rescue the penumbra by promoting neovascularization in cerebral I/R models. These findings suggest that ARBs have potential to become a novel category of neuroprotecting agents for clinical treatment of AIS. Therefore, this review primarily provides a theoretical foundation and practical evidence for the future clinical utilization of ARBs as neuroprotective agents following reperfusion therapy for AIS. It outlines the role of cerebral I/R injury through the AT1R pathway and highlights the research progress made on ARBs in I/R models.},
}

@article {pmid41383445,
year = {2024},
author = {Zhu, Y and Liao, L and Gao, S and Tao, Y and Huang, H and Fang, X and Yuan, C and Gao, C},
title = {Neuroprotective effects of repetitive transcranial magnetic stimulation on Alzheimer's disease: Undetermined therapeutic protocols and mechanisms.},
journal = {Neuroprotection (Chichester, England)},
volume = {2},
number = {1},
pages = {16-32},
pmid = {41383445},
issn = {2770-730X},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by gradual deterioration of cognitive functions, for which an effective treatment is currently unavailable. Repetitive transcranial magnetic stimulation (rTMS), a well-established noninvasive brain stimulation method, is utilized in clinical settings to address various neuropsychiatric conditions, such as depression, neuropathic pain, and poststroke dysfunction. Increasing evidence suggests that rTMS may enhance cognitive abilities in individuals with AD. However, its optimal therapeutic protocols and precise mechanisms are currently unknown, impeding its clinical implementation. In the present review, we aimed to summarize and discuss the efficacy-related parameters in rTMS treatment, encompassing stimulus frequency, stimulus pattern, stimulus intensity, and the configuration of the stimulus coil. Furthermore, we reviewed promising rTMS therapeutic protocols involving various combinations of these factors, that were examined in clinical studies. Based on our analysis, we propose that a multisite high-frequency rTMS (HF-rTMS) regimen has value in AD therapy, and that promising single-site protocols, such as HF-rTMS, applied over the left dorsolateral prefrontal cortex, precuneus, or cerebellum are required to be validated in larger clinical studies. Lastly, we provide a comprehensive review of the potential mechanisms underlying the neuroprotective effects of rTMS on cognition in AD in terms of brain network modulation as well as cellular and molecular reactions. In conclusion, the interaction of diverse mechanisms may be responsible for the total therapeutic effect of rTMS on AD. This review provides theoretical and practical evidence for the future clinical application and scientific research of rTMS in AD.},
}

@article {pmid41379906,
year = {2025},
author = {Zhang, L and Li, L and Cao, P and Yang, J and Zaiane, OR and Wang, F},
title = {An Efficient Transfer Learning With Prompt Learning for Brain Disorders Diagnosis.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2025.3625375},
pmid = {41379906},
issn = {2168-2208},
abstract = {The limited availability of training data significantly restricts the performance of deep supervised models for brain disease diagnosis. It is crucial to develop a learning framework through cross-disease transfer learning that can extract more information from the limited data. To address this challenge, we concentrate on prompt learning and endeavor to extend its application to the brain networks. Specifically, we propose a novel prompt learning framework called BPformer, which integrates knowledge transferred across diseases via specific prompts while keeping the original architecture of BPformer unchanged. The specific prompts incorporate 1) a mask prompt to determine whether the edges are noisy or discriminating, 2) disorder prompts for modeling consistent and disorder-specific knowledge, and 3) adaptive instance-level prompts to account for inter-individual variations. We evaluate BPformer on the private center Nanjing Medical University dataset, the public Autism Brain Imaging Data Exchange dataset, and the public Alzheimer's Disease Neuroimaging Initiative dataset. We demonstrate the effectiveness of the proposed model across various disease classification tasks, including major depressive disorder, bipolar disorder, alzheimer's disease, and autism spectrum disorder diagnoses. In addition, the proposed method enables disease interpretability and subtype analysis, empowering physicians to provide patients with more accurate and fine-grained treatment plans.},
}

@article {pmid41379352,
year = {2025},
author = {Mohanty, R and Wheatley, S and Chiotis, K and Marseglia, A and Westman, E and , },
title = {Distinct cerebrovascular pathways underlying Alzheimer's disease-related neurodegeneration.},
journal = {Acta neuropathologica},
volume = {150},
number = {1},
pages = {64},
pmid = {41379352},
issn = {1432-0533},
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/complications ; Female ; Male ; Aged, 80 and over ; Aged ; *Brain/pathology/diagnostic imaging ; *Cerebrovascular Disorders/pathology/diagnostic imaging ; White Matter/pathology ; Cerebrovascular Circulation/physiology ; Neuroimaging ; Cerebral Amyloid Angiopathy/pathology ; Arteriolosclerosis/pathology ; },
abstract = {The etiology of cerebrovascular pathology is heterogeneous. Independent or synergistic role of this pathology relative to Alzheimer's disease (AD) pathology is necessary to clarify distinct neurodegenerative pathways. We evaluated the interplay of various cerebrovascular markers postmortem and their in vivo neuroimaging, clinical and neuropathologic correlates using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). In 109 individuals, postmortem cerebrovascular pathology (atherosclerosis of the circle of Willis, cerebral amyloid angiopathy [CAA], arteriolosclerosis, white matter rarefaction, old infarcts, microinfarcts, hemorrhages, other ischemic/vascular changes) was characterized. Additionally, we assessed in vivo neuroimaging (cortical thickness, subcortical volume, white matter lesion burden, glucose standardized uptake value ratio, fractional anisotropy of white matter tracts, cerebral blood flow), cognitive, and neuropathologic measures (atrophy, AD pathology and copathologies including Lewy body, TDP-43, hippocampal sclerosis). The study sample had mean (standard deviation) age of 82.9 (7.2) years and included 29 women (27%) and 84 (77%) with intermediate/high AD neuropathologic change. Arteriolosclerosis and CAA emerged as dominant cerebrovascular markers using multiple correspondence analysis. More severe arteriolosclerosis was explained by higher white matter lesion burden and greater postmortem hippocampal atrophy (β = 143.2, 95% CI 63.9 to 230.1, p = 0.0003), but not AD pathology. More severe CAA was explained by fractional anisotropy (β = - 20, 95% CI - 41.5 to -3.1, p = 0.02) adjusted for AD pathology and reduced integrity of superior cerebellar peduncle, posterior thalamic radiation, and sagittal stratum tracts (rho < - 0.6, false discovery rate corrected p < 0.05). More severe CAA was also explained by cortical atrophy and AD pathology (β = 0.6, 95% CI 0.2 to 1.2, p = 0.007), and associated with poorer memory (β = - 0.2, 95% CI - 0.3 to -0.09, p = 0.0009). Results demonstrate two dominant cerebrovascular pathways. An arteriolosclerosis-driven pathway is unspecific to AD pathology, whereas a CAA-driven pathway is specific to AD pathology. Cerebrovascular pathology is associated with AD pathology in an etiology-dependent manner which may influence eligibility for treatment or treatment-emergent adverse events in disease-modifying therapies for AD.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging/complications
Female
Male
Aged, 80 and over
Aged
*Brain/pathology/diagnostic imaging
*Cerebrovascular Disorders/pathology/diagnostic imaging
White Matter/pathology
Cerebrovascular Circulation/physiology
Neuroimaging
Cerebral Amyloid Angiopathy/pathology
Arteriolosclerosis/pathology

@article {pmid41379219,
year = {2025},
author = {Taylor, LW and Simzer, EM and Young, LFP and Holt, K and Spires-Jones, TL and Durrant, CS},
title = {Confirmation of p-tau Ser356's association with Alzheimer's disease pathology and lowering in response to WZ4003 treatment in brain slice cultures. Reply to: "Phospho-tau Ser356 is mostly confined to pre-NFT neurons in Alzheimer's pathology".},
journal = {Acta neuropathologica},
volume = {150},
number = {1},
pages = {63},
pmid = {41379219},
issn = {1432-0533},
support = {UKDRI-Edin005//UK Dementia Research Institute/ ; RADF-2019a-001//Race Against Dementia/ ; AS-PG-21-006/ALZS_/Alzheimer's Society/United Kingdom ; },
}

@article {pmid41378779,
year = {2025},
author = {Begines, P and Fernández-Bolaños, JG and López, Ó},
title = {An updated patent review of acetylcholinesterase inhibitors for the treatment of alzheimer's disease (2021 - present).},
journal = {Expert opinion on therapeutic patents},
volume = {},
number = {},
pages = {},
doi = {10.1080/13543776.2025.2602702},
pmid = {41378779},
issn = {1744-7674},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with a complex and not fully elucidated etiology. An exponential rise in its incidence underscores the urgent need for effective therapeutic strategies. AD imposes a significant economic burden on public healthcare systems and on patient's families.

AREAS COVERED: This manuscript focuses on the review of potent acetylcholinesterase (AChE) inhibitors, either through chemical synthesis or isolation from natural sources, aimed at restoring acetylcholine levels. Most of the compounds discussed act as multitarget agents and are categorized into four groups: drug derivatives (9 patents), heterocyclic scaffolds (16 patents), natural products from plant extracts (12 patents), and synthetic compounds inspired by natural templates (18 patents).

EXPERT OPINION: AChE inhibition remains a compelling target in AD drug design, as it enhances acetylcholine levels and can alleviate cognitive decline. Furthermore, inhibitors that interact with the peripheral anionic site (PAS) of AChE may reduce β-amyloid self-aggregation, thereby preventing the deposition of neurotoxic peptides in the brain. However, targeting AChE alone is insufficient for the development of effective therapeutics. A multitarget approach, combining AChE inhibition with pharmacophores addressing β-amyloid aggregation, neuroinflammation, oxidative stress, and other pathological hallmarks, holds greater promise for the development of more efficient anti-Alzheimer's agents.},
}

@article {pmid41378217,
year = {2025},
author = {Li, W and Huang, W and Zhou, P and Yao, Y and Cai, B and Ye, S},
title = {Sporoderm-removed ganoderma lucidum spore powder (S-GLSP) alleviates neuroinflammation injury by regulating microglial polarization through inhibition of NLRP3 inflammasome activation.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1690192},
pmid = {41378217},
issn = {1663-9812},
abstract = {INTRODUCTION: Sporoderm-Removed Ganoderma lucidum Spore Powder (S-GLSP), derived from the spores of the medically valued fungus Ganoderma lucidum, exhibits diverse pharmacological activities and shows considerable potential in the treatment of Alzheimer's disease (AD). However, its underlying mechanisms of action remain incompletely elucidated. This study aims to investigate the protective effects of S-GLSP against AD and to explore the molecular mechanisms involved.

MATERIALS AND METHODS: The chemical profile of S-GLSP extract was characterized using LC-MS/MS. Alzheimer's disease models were established both in vivo and in vitro: a rat model was induced by D-galactose combined with intracerebroventricular injection of Aβ, while a cellular model was stimulated with LPS. The neuroprotective effects of S-GLSP were assessed through behavioral tests and hematoxylin-eosin (HE) staining. Immunofluorescence staining, Western blot (WB), RT-qPCR, and ELISA were employed to evaluate microglial polarization and NLRP3 inflammasome activation. Cell viability was measured using MTT and EdU assays. Finally, NLRP3 knockdown was performed to verify whether S-GLSP modulates microglial polarization via regulation of the NLRP3 inflammasome.

RESULTS: A total of 42 chemical compounds were identified in S-GLSP, including flavonoids, alkaloids, terpenoids, saccharides, phenolics, fatty acids, nucleosides, amino acids, and other. S-GLSP treatment alleviated neuronal damage, improved learning and memory deficits, and reduced the expression of phosphorylated tau (p-tau) in AD model rats. Further experiments in vitro and in vivo showed that S-GLSP downregulated M1 phenotypic markers (CD86, iNOS, TNF-α) and upregulated M2 markers (CD206, Arg-1, IL-10). Moreover, S-GLSP inhibited NLRP3 inflammasome activation and regulated the secretion of IL-1β and IL-18, effects that were consistent with those observed following NLRP3 knockdown.

CONCLUSION: Our findings demonstrate that S-GLSP alleviates Alzheimer's disease pathology by inhibiting NLRP3 inflammasome activation, promoting a shift in microglial polarization from the M1 to the M2 phenotype, and modulating the release of inflammatory cytokines. This study provides novel mechanistic insights into the therapeutic potential of S-GLSP for AD.},
}

@article {pmid41377997,
year = {2025},
author = {Monteiro, R and Dunn, JT and Rodriguez, G and Fisher, DW and Dong, H},
title = {Targeting central immune signaling enhances the effects of methylphenidate in alleviating apathy-like behavior in 5xFAD mice.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8031077/v1},
pmid = {41377997},
issn = {2693-5015},
abstract = {Alzheimer's disease (AD) is frequently accompanied by neuropsychiatric symptoms (NPS), among which apathy, one of the most prevalent and burdensome, accelerates cognitive decline and disease progression, yet its molecular underpinnings remain unclear. Our previous RNA-sequencing of AD subjects revealed abnormal immune gene expression uniquely associated with apathy. In this study, we investigated whether these changes are also linked to apathy-like behavior in 5xFAD mice, and whether administration of C3a receptor antagonist SB290157, alone or with methylphenidate, modifies these behaviors. We first validated the expression of apathy-related immune hub genes identified in human AD in the prefrontal cortex (PFC) of 16-month-old 5xFAD mice using RT-qPCR. Separate cohorts of similarly aged 5xFAD and WT mice then received SB290157 and/or methylphenidate for two weeks. Results indicate that increased immune-related genes, including Tyrobp, C3 , C3ar , C1qa , C1qb , and C1qc expression, were strongly correlated with apathy-like behavior in 5xFAD mice. Combined SB290157 and methylphenidate treatment significantly improved nest-building behavior, reduced C3 and C3ar protein expression, as well as restored dendritic spine density in the PFC. Our results confirm complement-mediated immune dysregulation is linked to apathy and suggest that co-targeting complement and catecholaminergic pathways may offer a novel therapeutic strategy for alleviating apathy in AD.},
}

@article {pmid41377219,
year = {2025},
author = {Pandey, P and Rajput, S and Gaur, T and Khandia, R and Gurjar, P},
title = {Animal models in human surgery and implant innovation: ethical considerations and scientific advancements.},
journal = {Annals of medicine and surgery (2012)},
volume = {87},
number = {12},
pages = {8291-8303},
pmid = {41377219},
issn = {2049-0801},
abstract = {The main aim of biological research is to bridge the gap between preclinical findings and clinical applications so that human health can be improved. Animal models are beneficial in replicating disease mechanisms, facilitating diagnosis, and assessing treatment efficacy for any disease. They play a vital role in drug discovery, toxicological assessments, dosage determination, and the evaluation of side effects, all while adhering to the ethical guidelines. These models are effectively used to treat a wide range of human diseases, including autoimmune disorders, rheumatoid arthritis, epilepsy, Alzheimer's disease, cardiovascular conditions, atherosclerosis, severe acute respiratory syndrome/Coronavirus disease 2019 (SARS/COVID-19), and diabetes. In disease modeling, they significantly contribute to drug development, medical device testing, tissue engineering, wound healing, and bone and cartilage regeneration. One cannot deny the fact that there are major significances of small and large animal models in scientific studies, apart from various advantages and challenges. Animal Models play an essential role in pharmaceutical research, biomedical research, genome editing, transgenic studies, and surgical applications. These models enable scientists and researchers to perform experiments that would be ethically or practically impossible in humans. In recent years, various animal species have been widely used to study health problems, including the 2019 Coronavirus pandemic, diabetes, and obesity. Mice, pigs, rabbits, rats, murine, primate, porcine, and aquatic models have played a crucial role in understanding the neurological, behavioral, cardiovascular, and oncological disorders while contributing to the development of innovative therapeutic approaches for their treatment. The studies in which pain is inflicted on animals must follow strict ethical standards. Whereas research involving painless animal death is often more accepted because of the fact that animals have limited awareness of their future. This review highlights the use of animal models in indispensable contributions to modern medicine and underscores their relevance in disease research, treatment development, and ethical considerations in experimental studies and their scientific advancements.},
}

@article {pmid41376208,
year = {2025},
author = {Li, X and Gao, W and Ye, Q and Li, H},
title = {The Role and Therapeutic Potential of the cGAS-STING Signaling Pathway in Alzheimer's Disease.},
journal = {Brain and behavior},
volume = {15},
number = {12},
pages = {e71130},
doi = {10.1002/brb3.71130},
pmid = {41376208},
issn = {2162-3279},
support = {LH2023H064// Natural Science Foundation of Heilongjiang Province of China/ ; 82105035//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Nucleotidyltransferases/metabolism ; *Signal Transduction/physiology ; *Membrane Proteins/metabolism ; Animals ; Autophagy/physiology ; },
abstract = {PURPOSE: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, posing a significant challenge to global public health. As a core signaling pathway in the mammalian innate immune system, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a pivotal role in maintaining intracellular homeostasis. This review aims to systematically elucidate the role and therapeutic potential of the cGAS-STING signaling pathway in AD, focusing on its involvement in key pathological processes and its relevance to AD risk factors.

METHOD: Through literature search, we summarized the molecular mechanisms of the cGAS-STING pathway and its dysregulation in AD, emphasizing the integrated evidence linking cGAS-STING to neuroinflammation, autophagy impairment, and neuronal death, as well as its interactions with aging, obesity, cardiovascular disease, and diabetes.

FINDINGS: The cGAS-STING pathway is critically involved in AD pathogenesis, contributing to neuroinflammation, defective autophagy, and neuronal loss. Its activation is associated with multiple AD risk factors, suggesting a broad influence on disease progression. Pharmacological inhibition of cGAS-STING shows promise in attenuating these pathological features in preclinical models.

CONCLUSION: The cGAS-STING signaling pathway plays a central regulatory role in the central nervous system, and its dysregulation promotes neuroinflammation and is closely associated with AD. This pathway forms a vicious cycle by integrating multiple pathological signals, including mitochondrial dysfunction and endoplasmic reticulum stress. Small-molecule inhibitors and natural products targeting this pathway have demonstrated significant efficacy in preclinical studies, providing a basis for developing disease-modifying therapies for AD. Future efforts should focus on multi-target combination strategies (e.g., STING inhibitors co-administered with Aβ/tau drugs) and dynamically deciphering pathway alterations across AD stages to advance personalized treatment approaches.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
*Nucleotidyltransferases/metabolism
*Signal Transduction/physiology
*Membrane Proteins/metabolism
Animals
Autophagy/physiology

@article {pmid41375579,
year = {2025},
author = {O'Donnell, AJ and Zhao, X and Parr, A and Aspinall, S and Anderson, TS},
title = {Early Outcomes of Lecanemab for Alzheimer's Disease in the Veterans Health Administration.},
journal = {Journal of clinical medicine},
volume = {14},
number = {23},
pages = {},
doi = {10.3390/jcm14238277},
pmid = {41375579},
issn = {2077-0383},
support = {N/A//Technology Enhancing Cognition and Health - Geriatric Research Education and Clinical Center (TECH-GRECC), VA Pittsburgh Healthcare System/ ; },
abstract = {Background/Objectives: While lecanemab (Leqembi) and several amyloid targeting therapies were approved for Alzheimer's disease, questions remain on real-world implementation, safety, and effectiveness. The objective of this study was to describe the uptake and early outcomes of Veterans initiating lecanemab. Methods: This retrospective cohort study included Veterans who initiated lecanemab in the Veteran's Health Administration (VHA) between October 2023 and July 2024. Treatment persistence and monitoring, change in Montreal Cognitive Assessment (MoCA) score, incidence of adverse events, including amyloid-related imaging abnormalities (ARIA), and healthcare utilization were analyzed at 7 months. Results: Overall, 32 Veterans (mean [SD] age 75.3 [6.0] years, 100% male, 97% white, 84% urban dwelling) initiated lecanemab. Seventeen patients (53%) had mild cognitive impairment, 15 (47%) had mild dementia; mean baseline MoCA score was 21.3 (SD 3.4). At 7 months following treatment initiation, we assessed process, safety, and effectiveness outcomes. Process outcomes: In all, 25 patients (78%) were persistent with treatment. Safety outcomes: Three patients (9%) experienced a stroke, and 7 (22%) experienced ARIA. Effectiveness outcomes: Only 12 (38%) patients had a MoCA completed by 7 months, and the mean change in MoCA was 0.0 (SD 3.7, p = 1.0). A follow-up amyloid positron emission tomography (PET) scan was completed by 9 (28%) patients, and 5 had reductions in amyloid. Conclusions: Initial observations in a small VHA cohort suggest that uptake of lecanemab was limited, and the finding that nearly 30% of patients experienced ARIA or stroke within 7 months of initiation underscores the importance of monitoring the lecanemab safety and effectiveness long-term. These early findings should be interpreted cautiously given the limited sample size and very limited follow-up MoCA data.},
}

@article {pmid41375185,
year = {2025},
author = {Vieira, RC and Nascimento, LA and Nascimento, AA and Alves, NRM and Nascimento, ÉCM and Martins, JBL},
title = {NCIVISION: A Siamese Neural Network for Molecular Similarity Prediction MEP and RDG Images.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {23},
pages = {},
doi = {10.3390/molecules30234589},
pmid = {41375185},
issn = {1420-3049},
support = {306682/2021-4 and 308419/2025-1//National Council for Scientific and Technological Development/ ; 00193-00000869/2021-31//Foundation for Research Support of the Federal District/ ; },
mesh = {*Neural Networks, Computer ; Static Electricity ; *Drug Discovery/methods ; Humans ; Cholinesterase Inhibitors/chemistry/pharmacology ; Protein Kinase Inhibitors/chemistry/pharmacology ; },
abstract = {Artificial neural networks in drug discovery have shown remarkable potential in various areas, including molecular similarity assessment and virtual screening. This study presents a novel multimodal Siamese neural network architecture. The aim was to join molecular electrostatic potential (MEP) images with the texture features derived from reduced density gradient (RDG) diagrams for enhanced molecular similarity prediction. On one side, the proposed model is combined with a convolutional neural network (CNN) for processing MEP visual information. This data is added to the multilayer perceptron (MLP) that extracts texture features from gray-level co-occurrence matrices (GLCM) computed from RDG diagrams. Both representations converge through a multimodal projector into a shared embedding space, which was trained using triplet loss to learn similarity and dissimilarity patterns. Limitations associated with the use of purely structural descriptors were overcome by incorporating non-covalent interaction information through RDG profiles, which enables the identification of bioisosteric relationships needed for rational drug design. Three datasets were used to evaluate the performance of the developed model: tyrosine kinase inhibitors (TKIs) targeting the mutant T315I BCR-ABL receptor for the treatment of chronic myeloid leukemia, acetylcholinesterase inhibitors (AChEIs) for Alzheimer's disease therapy, and heterodimeric AChEI candidates for cross-validation. The visual and texture features of the Siamese architecture help in the capture of molecular similarities based on electrostatic and non-covalent interaction profiles. Therefore, the developed protocol offers a suitable approach in computational drug discovery, being a promising framework for virtual screening, drug repositioning, and the identification of novel therapeutic candidates.},
}

*Neural Networks, Computer
Static Electricity
*Drug Discovery/methods
Humans
Cholinesterase Inhibitors/chemistry/pharmacology
Protein Kinase Inhibitors/chemistry/pharmacology

@article {pmid41375178,
year = {2025},
author = {Tsopka, IC and Pontiki, E and Sigala, I and Nikolakaki, E and Prousis, KC and Hadjipavlou-Litina, D},
title = {Design, Synthesis, Biological Evaluation, and In Silico Studies of Novel Multitarget Cinnamic Acid Hybrids.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {23},
pages = {},
doi = {10.3390/molecules30234582},
pmid = {41375178},
issn = {1420-3049},
mesh = {*Cinnamates/chemistry/pharmacology/chemical synthesis ; Humans ; *Drug Design ; Antioxidants/pharmacology/chemistry/chemical synthesis ; Anti-Inflammatory Agents/pharmacology/chemical synthesis/chemistry ; Lipoxygenase Inhibitors/pharmacology/chemical synthesis/chemistry ; Lipid Peroxidation/drug effects ; Molecular Docking Simulation ; Cyclooxygenase Inhibitors/pharmacology/chemical synthesis/chemistry ; Computer Simulation ; Structure-Activity Relationship ; Nitric Oxide Donors/chemistry/pharmacology/chemical synthesis ; Nitric Oxide ; Lipoxygenase/metabolism ; Molecular Structure ; Cell Line, Tumor ; Cyclooxygenase 2/metabolism/chemistry ; },
abstract = {Chronic inflammation is implicated in the development of various multifactorial diseases, including cancer, diabetes, arthritis, cardiovascular disorders, Alzheimer's disease, and autoimmune diseases. The enzymes that play a key role in the onset of the inflammation are cyclooxygenases (COXs) and lipoxygenases (LOXs). In recent years, cinnamic acid hybrid molecules, particularly those incorporating a nitric oxide (NO) donor moiety, have attracted considerable attention as potential pharmacological agents for the treatment of multifactorial diseases. In the present study, novel cinnamic acid-nitric oxide (NO) donor hybrids were synthesized as multitarget agents and evaluated for their antioxidant, anti-inflammatory, and cytotoxic properties. In particular, hybrids 5a-i, 6a-i, 9a-i, and 11 were synthesized and evaluated as lipid peroxidation and LOX inhibitors, while selected molecules were further tested as COX-1 and COX-2 inhibitors. Hybrids 6a-i, 9a-i, and 11 that contain a NO donor moiety, were additionally tested as albumin denaturation inhibitors and for their ability to release NO. The results indicated that compound 9a is a promising multitarget agent, exhibiting the lowest IC50 for LOX inhibition, significant antioxidant activity, and the highest NO donor potency. Furthermore, compound 9e demonstrated significant inhibitory activity against both COX-2 and LOX, suggesting its potential as a dual COX-LOX inhibitor. Additionally, compound 6i exhibited the strongest cytotoxic activity among the tested compounds, with EC50 values ranging from 36 to 45 μM across multiple cancer cell lines. All synthesized compounds were also evaluated through in silico studies.},
}

*Cinnamates/chemistry/pharmacology/chemical synthesis
Humans
*Drug Design
Antioxidants/pharmacology/chemistry/chemical synthesis
Anti-Inflammatory Agents/pharmacology/chemical synthesis/chemistry
Lipoxygenase Inhibitors/pharmacology/chemical synthesis/chemistry
Lipid Peroxidation/drug effects
Molecular Docking Simulation
Cyclooxygenase Inhibitors/pharmacology/chemical synthesis/chemistry
Computer Simulation
Structure-Activity Relationship
Nitric Oxide Donors/chemistry/pharmacology/chemical synthesis
Nitric Oxide
Lipoxygenase/metabolism
Molecular Structure
Cell Line, Tumor
Cyclooxygenase 2/metabolism/chemistry

@article {pmid41374080,
year = {2025},
author = {Kimble, R and Shannon, OM},
title = {Can Beetroot (Beta vulgaris) Support Brain Health? A Perspective Review on Alzheimer's Disease.},
journal = {Nutrients},
volume = {17},
number = {23},
pages = {},
doi = {10.3390/nu17233790},
pmid = {41374080},
issn = {2072-6643},
mesh = {Humans ; *Alzheimer Disease/prevention & control ; *Beta vulgaris/chemistry ; *Brain/drug effects ; Antioxidants/pharmacology ; Nitrates/pharmacology ; Oxidative Stress/drug effects ; Neuroprotective Agents/pharmacology ; Animals ; Polyphenols/pharmacology ; Betalains/pharmacology ; },
abstract = {Alzheimer's disease (AD), the leading cause of dementia, has limited treatment options despite extensive pharmacological research. This has increased interest in dietary strategies that act across multiple pathological mechanisms. Beetroot (Beta vulgaris), known for its cardiovascular and metabolic benefits, contains a distinctive combination of bioactive compounds including inorganic nitrate, betalains, and polyphenols. Together these constituents influence vascular function, oxidative stress, mitochondrial efficiency, inflammation, and the microbiota. Previous reviews have typically focused on dietary nitrate in dementia prevention or have examined nitrate and betalains separately. In contrast, this review synthesises evidence on beetroot as a combined neuroprotective food. Preclinical data indicate that beetroot and its key constituents enhance antioxidant defences, support neuronal bioenergetics, and modulate cholinergic and inflammatory pathways. Human studies further suggest that nitrate-rich beetroot can improve cerebral blood flow and vascular responsiveness, and that higher intakes of plant-derived nitrate are associated with reduced cognitive decline. However, findings are inconsistent, most trials are small and short in duration, and research directly involving people with AD is scarce. By integrating vascular, antioxidant, and microbiome perspectives, this review identifies beetroot as a promising yet underexplored dietary candidate for AD management. Further mechanistic studies and multidomain approaches combining metagenomics, biomarkers, neuroimaging, and cognitive outcomes are needed.},
}

Humans
*Alzheimer Disease/prevention & control
*Beta vulgaris/chemistry
*Brain/drug effects
Antioxidants/pharmacology
Nitrates/pharmacology
Oxidative Stress/drug effects
Neuroprotective Agents/pharmacology
Animals
Polyphenols/pharmacology
Betalains/pharmacology

@article {pmid41374061,
year = {2025},
author = {Calzoni, E and Cusumano, G and Bertoldi, A and Alabed, HBR and Pellegrino, RM and Buratta, S and Urbanelli, L and Zengin, G and Emiliani, C},
title = {Rhubarb-Derived Extracellular Vesicles Mitigate Oxidative Stress and Metabolic Dysfunction in an Alzheimer's Cellular Model.},
journal = {Nutrients},
volume = {17},
number = {23},
pages = {},
doi = {10.3390/nu17233771},
pmid = {41374061},
issn = {2072-6643},
support = {CUP J97G22000170005//National Innovation Ecosystem grant ECS00000041/ ; },
mesh = {*Oxidative Stress/drug effects ; *Rheum/chemistry ; *Alzheimer Disease/metabolism ; Humans ; *Extracellular Vesicles/metabolism ; *Antioxidants/pharmacology ; Energy Metabolism/drug effects ; Reactive Oxygen Species/metabolism ; },
abstract = {Background/Objectives: Extracellular vesicles derived from edible plants have emerged as bioactive nanostructures with potential therapeutic and nutraceutical properties and are currently being investigated as natural carriers for the treatment of oxidative stress-induced damage and oxidative stress-related diseases, including neurodegenerative disorders such as Alzheimer's disease (AD). Recent studies suggest that PDEVs exhibit high stability within the gastrointestinal tract and selective tissue-targeting abilities, facilitating the efficient delivery of bioactive molecules. Methods: This study investigates the antioxidant effects of Rheum rhabarbarum-derived EVs by assessing the antioxidant activity through different in vitro assays and their effects on oxidative stress and energy metabolism in the cellular model of Alzheimer's disease. Results: Rhubarb-derived EVs showed measurable antioxidant capacity in chemical assays and were non-toxic under the tested conditions. Treatment reduced intracellular ROS levels and modulated oxidative stress-related proteins, suggesting a potential protective effect against oxidative damage. Moreover, metabolic analysis revealed a decrease in glycolytic activity, indicating a potential restoration of cellular bioenergetic homeostasis. Conclusions: These results provide preliminary evidence supporting the nutraceutical interest of rhubarb-derived EVs in counteracting oxidative stress, while further studies will be needed to confirm their biological relevance and therapeutic potential.},
}

*Oxidative Stress/drug effects
*Rheum/chemistry
*Alzheimer Disease/metabolism
Humans
*Extracellular Vesicles/metabolism
*Antioxidants/pharmacology
Energy Metabolism/drug effects
Reactive Oxygen Species/metabolism

@article {pmid41373689,
year = {2025},
author = {Brehar, FM and Costea, D and Tataru, CP and Rădoi, MP and Ciurea, AV and Munteanu, O and Tulin, A},
title = {The Fluidic Connectome in Brain Disease: Integrating Aquaporin-4 Polarity with Multisystem Pathways in Neurodegeneration.},
journal = {International journal of molecular sciences},
volume = {26},
number = {23},
pages = {},
doi = {10.3390/ijms262311536},
pmid = {41373689},
issn = {1422-0067},
mesh = {*Aquaporin 4/metabolism ; Humans ; Animals ; Blood-Brain Barrier/metabolism ; *Brain Diseases/metabolism/pathology ; *Connectome/methods ; Astrocytes/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Glymphatic System/metabolism ; },
abstract = {The way in which Aquaporin-4 (AQP4) is localized on the astrocytes' surface-i.e., with AQP4 channels predominantly located on the endfeet of astrocytes near the blood vessels-represents an important structural element for maintaining brain fluid homeostasis. In addition to this structural function, AQP4 polarity also facilitates glymphatic transport, the maintenance of the blood-brain barrier (BBB) functions, ion buffering, and neurotransmitter removal, and helps regulate neurovascular communications. The growing body of literature suggests that the loss of AQP4 polarity-a loss in the organization of AQP4 channels to the perivascular membrane-is associated with increased vascular, inflammatory, and metabolic disturbances in the context of many neurological diseases. As a result, this review attempts to synthesize both experimental and clinical studies to highlight that AQP4 depolarization often occurs in conjunction with early signs of neurodegeneration and neuroinflammation; however, we are aware that the loss of AQP4 polarity is only one factor in a complex pathophysiological environment. This review examines the molecular structure responsible for maintaining the polarity of AQP4-such as dystrophin-syntrophin complexes, orthogonal particle arrays, lipid microdomains, trafficking pathways, and transcriptional regulators-and describes how the vulnerability of these systems to various types of vascular stress, inflammatory signals, energy deficits, and mechanical injury can lead to a loss of AQP4 polarity. Furthermore, we will explore how a loss of AQP4 polarity can lead to the disruption of perivascular fluid movement, changes in blood-brain barrier morphology, enhanced neuroimmune activity, changes in ionic and metabolic balance, and disruptions in the global neural network synchronization. Importantly, we recognize that each of these disruptions will likely occur in concert with other disease-specific mechanisms. Alterations in AQP4 polarity have been observed in a variety of neurological disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis, traumatic brain injury, and glioma; however, we also observe that the same alterations in fluid regulation occur across all of these different diseases, but that no single upstream event accounts for the alteration in polarity. Ultimately, we will outline emerging therapeutic avenues to restore perivascular fluid transport, and will include molecular-based therapeutic agents designed to modify the anchoring of AQP4, methods designed to modulate the state of astrocytes, biomaterials-based drug delivery systems, and therapeutic methods that leverage dynamic modulation of the neurovascular interface. Future advances in multi-omic profiling, spatial proteomics, glymphatic imaging, and artificial intelligence will allow for earlier identification of AQP4 polarity disturbances and potentially allow for the development of more personalized treatment plans. Ultimately, by linking these concepts together, this review aims to frame AQP4 polarity as a modifiable aspect of the "fluidic connectome", and highlight its importance in maintaining overall brain health across disease states.},
}

*Aquaporin 4/metabolism
Humans
Animals
Blood-Brain Barrier/metabolism
*Brain Diseases/metabolism/pathology
*Connectome/methods
Astrocytes/metabolism
*Neurodegenerative Diseases/metabolism/pathology
Glymphatic System/metabolism

@article {pmid41373648,
year = {2025},
author = {Ishikawa, K and Fujikawa, R and Okita, K and Kimura, F and Watanabe, T and Katsurabayashi, S and Iwasaki, K},
title = {Microglia in Brain Aging and Age-Related Diseases: Friends or Foes?.},
journal = {International journal of molecular sciences},
volume = {26},
number = {23},
pages = {},
doi = {10.3390/ijms262311494},
pmid = {41373648},
issn = {1422-0067},
support = {24K18288 (R.F.), 23K27496 (S.K.) and 24H02336 (S.K.)//JSPS KAKENHI/ ; },
mesh = {Humans ; *Microglia/metabolism/pathology ; *Aging/pathology ; *Brain/pathology/metabolism ; Animals ; *Neurodegenerative Diseases/pathology/metabolism ; },
abstract = {With the global rise in population aging, establishing effective strategies for the prevention and treatment of age-related neurodegenerative diseases, as well as their prodromal stage of cognitive frailty, has become an urgent challenge. Recent studies have revealed that the neural basis of both frailty and age-related disorders is closely associated with chronic neuroinflammation and impaired clearance of cellular debris, processes that are primarily regulated by microglia, the resident immune cells of the brain. As aging progresses, microglia exhibit reduced surveillance and motility, diminished phagocytic efficiency, and transition into a proinflammatory, hyperresponsive state. Such maladaptive microglia contribute to synaptic loss, white matter deterioration, and the spread of neurodegenerative pathology. Conversely, single-cell transcriptomic studies have identified distinct microglial subsets, including CD11c[+] microglia, which show upregulation of lysosomal and lipid metabolism pathways, enhanced debris clearance, and elevated neurotrophic factor expression. These features suggest that certain microglial populations adopt protective or adaptive phenotypes that preserve neural integrity. However, under chronic inflammation or pathological conditions, even protective microglia may become inflammation-promoting. This review summarizes current evidence on microglial changes in aging, frailty, and neurodegeneration, emphasizing their dual roles and discussing strategies that modulate microglial function to maintain brain health and prevent or treat frailty and age-related diseases.},
}

Humans
*Microglia/metabolism/pathology
*Aging/pathology
*Brain/pathology/metabolism
Animals
*Neurodegenerative Diseases/pathology/metabolism

@article {pmid41373506,
year = {2025},
author = {Muzaffar, S and Tyagi, A and Pugazhenthi, S},
title = {Therapeutic Potential of Irisin in Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {26},
number = {23},
pages = {},
doi = {10.3390/ijms262311348},
pmid = {41373506},
issn = {1422-0067},
support = {NEUD-004-07F//United States Department of Veterans Affairs/ ; },
mesh = {Humans ; *Fibronectins/metabolism/therapeutic use/genetics ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; Exercise ; },
abstract = {Irisin is a myokine secreted by muscle in response to exercise. It is derived from a transmembrane protein called fibronectin type III domain-containing protein 5 (FNDC5). The Fndc5 gene is expressed in several tissues, including skeletal muscle, brain, adipose tissue, heart, kidney, and lung. Irisin is cleaved from FNDC5 protein by the enzyme furin and released into circulation. In addition to exercise, several drugs have been shown to increase the production of irisin. Administration of exogenous irisin mimics the beneficial actions of exercise. Irisin can cross the blood-brain barrier and exert neuroprotective actions in the brain. It has been shown to reverse Alzheimer's pathologies in clinical and animal studies. Irisin also exerts protective effects against obesity, diabetes, and cardiovascular disease, diseases that often coexist with aging AD patients. Multiple approaches have been taken to suggest that exercise may act through irisin. Studies have provided direct evidence linking the two using Fndc5 gene deletion and irisin antibodies. Irisin binds to αVβ1/β5 integrins to mediate the activation of integrin-FAK pathways. While exercise as a lifestyle modification for healthy aging is well recognized, it may present limitations in some aging populations, especially those with disease conditions, including Parkinson's disease. Administration of exogenous irisin or small molecules that increase the expression of endogenous irisin or facilitate its actions are some alternate approaches that can mimic the beneficial actions of exercise. This review discusses the therapeutic potential of irisin in the treatment of neurodegenerative and other aging-associated diseases.},
}

Humans
*Fibronectins/metabolism/therapeutic use/genetics
Animals
*Neurodegenerative Diseases/metabolism/drug therapy
Exercise

@article {pmid41373466,
year = {2025},
author = {Adamski, P and Szeleszczuk, Ł and Gackowski, M and Grodner, B},
title = {Creatine and Taurine as Novel Competitive Inhibitors of Acetylcholinesterase: A Biochemical Basis for Nutritional Modulation of Brain Function.},
journal = {International journal of molecular sciences},
volume = {26},
number = {23},
pages = {},
doi = {10.3390/ijms262311309},
pmid = {41373466},
issn = {1422-0067},
mesh = {*Taurine/pharmacology/chemistry ; *Cholinesterase Inhibitors/pharmacology/chemistry ; *Acetylcholinesterase/metabolism/chemistry ; Molecular Docking Simulation ; Humans ; *Creatine/pharmacology/chemistry ; *Brain/drug effects/physiology/metabolism ; Kinetics ; },
abstract = {Acetylcholinesterase (AChE) is a key enzyme responsible for terminating cholinergic neurotransmission by hydrolyzing acetylcholine. While clinically approved AChE inhibitors such as donepezil, rivastigmine, and galantamine are used in the symptomatic treatment of Alzheimer's disease and related dementias, little is known about the modulatory effects of common dietary compounds on AChE activity. In this study, we investigated the influence of creatine (CR) and taurine (TA)-two widely consumed nutritional supplements with reported neuroprotective and cognitive-enhancing properties-on AChE. Enzyme kinetics were evaluated using a modified Ellman's method, and Lineweaver-Burk analyses revealed that both CR and TA act as competitive inhibitors. Calculated parameters (Km, Vmax), inhibition constants (Ki), and half maximal inhibitory concentrations (IC50) consistently indicated stronger potency for CR (IC50 = 0.0056 ± 0.00018 mM) compared to TA (IC50 = 0.0097 ± 0.00035 mM). To complement the experimental data, molecular docking was performed using two crystal structures of human AChE. Docking confirmed that both ligands preferentially occupy the active-site region in a manner consistent with competitive inhibition, with CR showing more favorable binding scores than TA. Although markedly weaker than clinical drugs, these findings provide the first biochemical and in silico evidence that CR and TA directly interact with AChE, suggesting subtle cholinergic modulation relevant to cognitive function and neuroprotection.},
}

*Taurine/pharmacology/chemistry
*Cholinesterase Inhibitors/pharmacology/chemistry
*Acetylcholinesterase/metabolism/chemistry
Molecular Docking Simulation
Humans
*Creatine/pharmacology/chemistry
*Brain/drug effects/physiology/metabolism
Kinetics

@article {pmid41372777,
year = {2025},
author = {Mi, F and Li, H and Pan, D and Yu, C},
title = {Effect of organismal rhythmic activity on Aβ clearance by the glymphatic system.},
journal = {European journal of medical research},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40001-025-03646-5},
pmid = {41372777},
issn = {2047-783X},
abstract = {Abnormal deposition of β-amyloid (Aβ) is a significant pathological feature of neurodegenerative diseases, particularly Alzheimer's disease (AD). The glymphatic system (GS) plays a crucial role in Aβ clearance. Various rhythmic activities of the organism dynamically influence Aβ clearance by modulating GS function. In this paper, we systematically review the mechanisms linking cardiovascular rhythms, respiratory rhythms, neural rhythms, circadian rhythms, and exercise patterns to Aβ clearance via the GS. Cardiovascular rhythms affect cerebral perfusion pressure and vascular pulsation to regulate GS transport efficiency; respiratory rhythms modulate intracranial pressure and cerebrospinal fluid (CSF) circulation through thoracic pressure variations; neural rhythms (including delta waves during non-rapid eye movement (NREM) sleep and neurovascular coupling) synchronize neuro-glial-vascular interactions to enhance GS clearance. Circadian rhythms coordinate these primary rhythms by regulating melatonin levels and cerebral blood flow, while exercise patterns adjust GS function via aquaporin-4 (AQP4) polarization. Additionally, we elaborate on the cascade effect of AD resulting from rhythmic dysregulation. A thorough understanding of how rhythmic activities impact Aβ clearance by the GS may offer new perspectives and potential intervention strategies for the prevention and treatment of AD through the concept of "synchronized multiple rhythms"-a novel framework that integrates multi-rhythm synergy. Clinically, this work provides a theoretical basis for developing targeted interventions, such as personalized exercise timing regimens, respiratory rhythm training, and closed-loop neurovascular feedback devices, to restore GS function in AD patients.},
}

@article {pmid41372196,
year = {2025},
author = {Du, M and Li, N and Li, T and Zhao, Z and Liu, H and Li, X and Gong, N and Duan, B and Wang, W and Jian, Y and Ma, W and Zhang, X and Wang, Y and Zhang, Z and Bai, Y and Wang, X and Wang, C and Liu, J and Guan, X and Zhou, F and Wang, W and Li, L and Zhu, X and Lei, Y and Duan, Y and Han, G and Wei, P and Gao, S and Wang, S and Chen, A and Huang, Y and Yang, H and Xue, X and Zhang, H},
title = {Chimeras co-targeting antigens and FcγRIIb trigger degradation of extracellular soluble proteins and pathological aggregates.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-025-67207-4},
pmid = {41372196},
issn = {2041-1723},
support = {82261138553//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82373898//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {While the clinical utility of conventional antibody therapies is undeniable, their therapeutic potential is often constrained high antigen loads and the recycling of antibody-antigen complexes via neonatal Fc receptor (FcRn). Here, we present a platform, based on a design similar to bispecific antibodies, FcγRIIb-Targeting Chimeras (FcRTAC). These constructs recognise antigens with one arm and bind FcγRIIb with the other arm to harness the unique endocytic properties of FcγRIIb to direct the recognized pathogenic antigens to lysosomes for irreversible degradation. The FcRTAC platform demonstrates broad therapeutic potential across multiple disease-relevant targets, including IgE, proprotein convertase subtilisin/kexin type 9 (PCSK9) and amyloid-β (Aβ). Notably, a single intravenous administration of blood brain barrier (BBB)-penetrating adeno-associated viral vector (AAV) encoding an Aβ-targeting FcRTAC construct achieves sustained therapeutic effects, establishing proof-of-concept for AAV-mediated delivery of an Aβ degrader as a strategy for Alzheimer's disease treatment. Our comprehensive investigation of binding properties of FcRTACs reveals critical molecular determinants of function and enables development of optimized engineering approaches. In summary, our approach represents a versatile therapeutic platform for treating diverse diseases ranging from autoimmune disorders to neurodegenerative conditions, while simultaneously serving as a user-friendly, plug-and-play research tool for extracellular protein knockout in basic biological research.},
}

@article {pmid41371839,
year = {2026},
author = {Kubohira, Y and Okano, N and Taharabaru, T and Ishimatsu, A and Era, T and Yanagihara, K and Ishikura, K and Nakagawa, Y and Higashi, T and Motoyama, K},
title = {A water-soluble β-cyclodextrin polymer reduces cholesterol accumulation and autophagy dysfunction in vitro and in Niemann-Pick type C disease model mice.},
journal = {Carbohydrate polymers},
volume = {374},
number = {},
pages = {124676},
doi = {10.1016/j.carbpol.2025.124676},
pmid = {41371839},
issn = {1879-1344},
mesh = {Animals ; *Cholesterol/metabolism ; *Niemann-Pick Disease, Type C/drug therapy/metabolism/pathology ; *Autophagy/drug effects ; Mice ; Humans ; *beta-Cyclodextrins/chemistry/pharmacology ; Disease Models, Animal ; *Cyclodextrins/chemistry/pharmacology ; Water/chemistry ; Cell Line, Tumor ; Solubility ; Cellulose ; },
abstract = {Niemann-Pick disease type C (NPC) and Alzheimer's disease (AD) are characterised by cognitive dysfunction and neurological impairment. In both diseases, the abnormal accumulation and disruption of cholesterol homeostasis in the brain may contribute to the pathogenesis and exacerbation of symptoms. Cyclodextrins (CDs) are attracting attention as therapeutic agents that can reduce free cholesterol in the brain. A water-soluble β-CD polymer (β-CDP) consisting of multiple β-CDs cross-linked by epichlorohydrin was recently developed and reportedly has improved safety and higher circulation time in the bloodstream. In this study, we evaluated the potential of β-CDP as a promising therapeutic agent for NPC and AD. β-CDP lowered free cholesterol levels and reversed autophagy dysfunction in cholesterol-accumulated human neuroblastoma cells. Longer circulation time in the bloodstream and reduced cholesterol accumulation in NPC mice were also observed after its subcutaneous administration. These results suggest that β-CDP may be a safe therapeutic agent in the treatment of NPC and AD.},
}

Animals
*Cholesterol/metabolism
*Niemann-Pick Disease, Type C/drug therapy/metabolism/pathology
*Autophagy/drug effects
Mice
Humans
*beta-Cyclodextrins/chemistry/pharmacology
Disease Models, Animal
*Cyclodextrins/chemistry/pharmacology
Water/chemistry
Cell Line, Tumor
Solubility
Cellulose

@article {pmid41371570,
year = {2025},
author = {Supasai, S and Suntaratti, P and Odton, M and Longji, T and Karananan, T and Yasom, S and Ampawong, S and Limpanont, Y and Mutirangura, A},
title = {HMGB1 Box A gene therapy reverses cognitive and neuropathological features in AlCl3/D-galactose rat model of Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115583},
doi = {10.1016/j.expneurol.2025.115583},
pmid = {41371570},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is pathologically defined by the accumulation of amyloid-β and tau pathology, resulting in progressive cognitive decline. Our previous work demonstrated that high mobility group box 1 (HMGB1): a pivotal regulator of … HMGB1 Box A plasmids alleviated cellular senescence and restored cognitive performance in aged rat models, supporting their therapeutic potential for neurodegenerative disorders such as AD. In this study, we investigated the efficacy of HMGB1 Box A gene therapy in an AD-like rat model chronically induced by AlCl3 and D-galactose. Following the onset of AD pathology, Box A plasmids were administered weekly at varying doses over eight weeks. Box A treatment significantly improved behavioral outcomes, including responsiveness, locomotor activity, and learning and memory performance. At the neuropathological level, Box A reduced hippocampal Aβ accumulation and tau pathology, restored neuronal density, and attenuated synaptic degeneration. Moreover, it suppressed hippocampal microgliosis, astrogliosis, and the expression of proinflammatory mediators. Box A also diminished markers of cellular senescence in the hippocampus. These findings demonstrate that HMGB1 Box A gene therapy confers multi-level neuroprotective effects in AD, from molecular and cellular restoration to behavioral recovery. This strategy holds strong promise as a disease-modifying treatment for AD, contributing to improved well-being by advancing therapeutic innovation to promote healthy aging and combat age-related neurodegenerative diseases.},
}

@article {pmid41370943,
year = {2025},
author = {Xu, J and He, Z and Pan, Y and Cao, B and Chen, G},
title = {Nanotherapeutic potential of Baicalein-encapsulated hUC-MSC exosomes in Alzheimer's disease: Modulating oxidative stress and neuroinflammation.},
journal = {Biomaterials advances},
volume = {181},
number = {},
pages = {214619},
doi = {10.1016/j.bioadv.2025.214619},
pmid = {41370943},
issn = {2772-9508},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by excessive amyloid-β (Aβ) accumulation, neuroinflammation, and oxidative stress. Exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSC@Exo) represent promising nanoscale carriers for targeted drug delivery. In this study, Baicalein (Bac), a potent antioxidant and anti-inflammatory flavonoid, was encapsulated into hUC-MSC-derived exosomes (Exo@Bac) to enhance its therapeutic efficacy. The neuroprotective potential of Exo@Bac was evaluated in a rat model of Aβ1-42-induced AD. Rats received intraperitoneal injections of Bac, hUC-MSC@Exo, or Exo@Bac, and cognitive performance was assessed using the passive avoidance test and Morris water maze. Exo@Bac treatment significantly improved memory deficits and elevated brain-derived neurotrophic factor (BDNF) expression compared to controls. Histopathological analyses revealed reduced neuronal damage and apoptosis, alongside decreased Aβ1-42 deposition in Exo@Bac-treated rats. Furthermore, Exo@Bac enhanced antioxidant defense (increased SOD), attenuated pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and lowered lipid peroxidation (MDA). Mechanistically, Exo@Bac promoted AMPK phosphorylation while suppressing NF-κB p65 signaling, indicating modulation of both oxidative stress and neuroinflammatory pathways. These findings demonstrate that Exo@Bac acts as a nanotherapeutic agent capable of mitigating AD pathology, highlighting its potential as a novel strategy for Alzheimer's disease therapy.},
}

@article {pmid41369702,
year = {2025},
author = {Hooshmandi, E and Rafiei, E and Owjfard, M and Mohammadi, Y and Koohpeyma, F and Simani, L and Safari, MS and Rai, SN and Ashjazadeh, N and Pandamooz, S and Bayat, M and Salehi, MS},
title = {Neuroprotective and Immunomodulatory effects of human hair follicle stem cells on streptozotocin-induced memory impairment in rats: insights into inflammation and neurotrophic mechanisms.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {178},
pmid = {41369702},
issn = {1573-4978},
support = {29005//Vice-Chancellor for Research, Shiraz University of Medical Sciences/ ; },
mesh = {Animals ; Male ; Rats ; Rats, Sprague-Dawley ; Streptozocin ; Humans ; *Memory Disorders/chemically induced/therapy/metabolism ; *Hair Follicle/cytology ; Hippocampus/metabolism ; Inflammation ; Stem Cell Transplantation/methods ; Alzheimer Disease/therapy ; Disease Models, Animal ; *Stem Cells/cytology/metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; Neuroinflammatory Diseases ; Neuroprotective Agents/pharmacology ; },
abstract = {BACKGROUND/OBJECTIVE: Alzheimer's disease (AD), a primary cause of dementia, involves cognitive decline and neuroinflammation. Human hair follicle stem cells (hHFSCs) have shown neuroprotective potential, but their effects on immune modulation, especially in xenogeneic transplantation, remain unclear. This study aimed to investigate the therapeutic potential of hHFSCs against memory impairment and neuroinflammation induced by streptozotocin (STZ) in male rats.

METHODS: Adult male Sprague-Dawley rats were intracerebroventricularly injected with STZ (3 mg/kg) to induce AD-like cognitive deficits. hHFSC transplantation (1 × 10[6]) was done on days 4, 14, and 21 post-surgery. Y-maze and Passive avoidance were used to assess memory. Hippocampal tissue was analyzed for mRNA expression of pro/anti-inflammatory factors and neurotrophic markers using quantitative RT-PCR. Histological evaluation quantified hippocampal pyramidal neurons and volume.

RESULTS: STZ significantly impaired memory in passive avoidance test, but not Y-maze. hHFSC significantly improved memory performance. mRNA analysis revealed elevated BDNF, TGFβ, and GFAP levels in the STZ group. The increased TGFβ and GFAP levels continued following hHFSC treatment, indicating a compensatory response. Moreover, pro-inflammatory factors (IL-1β, IL-6, and TNFα) were upregulated following hHFSC therapy, suggesting persistent neuroinflammation. hHFSC led to anti-inflammatory effects through the elevation of IL-10. In addition, hHFSCs significantly reduced hippocampal atrophy and neuronal loss induced by STZ.

CONCLUSION: hHFSCs exhibit partial neuroprotective effects against STZ-induced memory impairment. The simultaneous upregulation of pro- and anti-inflammatory markers underscores the complexity of the inflammatory response in this xenogeneic model. Future investigations should consider immunocompromised models or immunosuppressive protocols better to isolate the therapeutic effects of hHFSCs from immune responses.},
}

Animals
Male
Rats
Rats, Sprague-Dawley
Streptozocin
Humans
*Memory Disorders/chemically induced/therapy/metabolism
*Hair Follicle/cytology
Hippocampus/metabolism
Inflammation
Stem Cell Transplantation/methods
Alzheimer Disease/therapy
Disease Models, Animal
*Stem Cells/cytology/metabolism
Brain-Derived Neurotrophic Factor/metabolism
Neuroinflammatory Diseases
Neuroprotective Agents/pharmacology

@article {pmid41369361,
year = {2025},
author = {Yu, SP and Gu, X and Jiang, MQ and Sastry, A and Wu, L and Li, Y and Wei, L},
title = {Combined Preventive and Preconditioning Treatments for the Comorbidity of Alzheimer's Disease and Ischemic Stroke in a GluN3A Knockout Mouse and a 5xFAD Mouse.},
journal = {Cells},
volume = {14},
number = {23},
pages = {},
doi = {10.3390/cells14231871},
pmid = {41369361},
issn = {2073-4409},
support = {AG067473, NS114221; RX001473 (VA); RX003865 (VA)//National Instutute of Health, USA, VA Research Administration, USA/ ; },
mesh = {Animals ; *Alzheimer Disease/prevention & control/complications ; *Ischemic Stroke/prevention & control/complications ; Mice ; *Receptors, N-Methyl-D-Aspartate/metabolism/genetics/deficiency ; Mice, Knockout ; Disease Models, Animal ; Memantine/pharmacology/therapeutic use ; Male ; Comorbidity ; Mice, Inbred C57BL ; },
abstract = {Alzheimer's disease (AD) and stroke have been identified as risk factors for each other. More than half of AD patients suffer stroke attacks and worse ischemic injuries. There has been a lack of research focus and clinical treatment for the comorbidity of these neurological disorders. AD and ischemic stroke share characteristic pathophysiology, including hyperactivities of excitatory neurons and NMDA receptors (NMDARs), excitotoxicity, and synapse/neurovascular destruction. Our recent investigations identified the deficiency of the NMDAR regulatory GluN3A (NR3A) subunit as a novel pathogenesis of sporadic AD. The present investigation tested a preemptive treatment to prevent AD development in two AD models and, in the meantime, to prime the susceptible brain against upcoming ischemic attacks. In the preclinical stage of 3-month-old GluN3A KO mice, an NMDAR-mediated sporadic AD model, and 5xFAD mice, an amyloid-based familial AD model, treatments with memantine (MEM), an NMDAR antagonist (10 mg/kg/day in drinking water) and a drug-free control were started when cognition of these mice was generally normal. Three months later, the mice were subjected to focal cerebral ischemic surgery, followed by continued 1.5-2.0 months of MEM or vehicle control. Morphological, pathological, and functional assessments were performed and compared at different time points. In both AD models, the early MEM treatment confined AD progression before and after stroke, reduced ischemia-induced brain injury, suppressed neuroinflammation, and improved locomotion, sensorimotor, psychological, and cognitive functions. This is the first report endorsing a shared mechanism of NMDAR hyperactivity in AD and stroke in AD models with distinctive risk factors. The dual therapeutic effects of the preemptive MEM treatment provide a disease-modifying possibility for individuals who are susceptible to sporadic or familial AD as well as ischemic stroke.},
}

Animals
*Alzheimer Disease/prevention & control/complications
*Ischemic Stroke/prevention & control/complications
Mice
*Receptors, N-Methyl-D-Aspartate/metabolism/genetics/deficiency
Mice, Knockout
Disease Models, Animal
Memantine/pharmacology/therapeutic use
Male
Comorbidity
Mice, Inbred C57BL

@article {pmid41368712,
year = {2025},
author = {He, Q and Xia, Y and Shen, Q and Huang, C and Nie, X and Hu, X and Tang, X},
title = {Relationships between sarcopenia and Alzheimer's disease: screening for mitochondria-related biomarkers.},
journal = {Computer methods in biomechanics and biomedical engineering},
volume = {},
number = {},
pages = {1-22},
doi = {10.1080/10255842.2025.2598656},
pmid = {41368712},
issn = {1476-8259},
abstract = {This study aims to identify mitochondrial-related biomarkers for sarcopenia and Alzheimer's disease (AD). Through the GEO database and machine learning algorithms, three diagnostic biomarkers (FKBP5, PRKAG1, and FBP2) were identified, and the constructed models showed good diagnostic accuracy in both internal and external datasets. Furthermore, multiple analyses such as GSEA, immune infiltration, and drug prediction were conducted. These findings provide new insights into shared pathological mechanisms and clinical diagnosis and treatment of sarcopenia and AD. Further clinical and experimental studies are needed to validate these results.},
}

@article {pmid41368444,
year = {2025},
author = {Pang, R and Jia, Q and Ma, C and Li, T and Bi, W and Wang, H and Liu, R and Chen, P and Lee, ES and Jiang, HB},
title = {Alzheimer's Disease: The Current and Emerging Treatment Approaches.},
journal = {Behavioural neurology},
volume = {2025},
number = {},
pages = {9627699},
pmid = {41368444},
issn = {1875-8584},
mesh = {*Alzheimer Disease/therapy/drug therapy ; Humans ; Genetic Therapy/methods ; Amyloid beta-Peptides/metabolism ; Animals ; Plaque, Amyloid ; Neurofibrillary Tangles/pathology ; Plant Extracts/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease characterized by amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs) as its main pathological features. It mainly manifests as cognitive dysfunction, and its pathological process may occur before symptom onset. However, the current drugs and methods for treating AD have unsatisfactory therapeutic outcomes. Therefore, finding a treatment that can inhibit the progression of AD by targeting its pathological features is an urgent need. This review summarizes the current traditional drugs that can delay the progression of AD and new drugs that act on the pathological characteristics of AD and highlights the potential value of related plant extracts. In addition, this review explores the application of different vectors, such as viral vectors and nanoparticles, in gene therapy and drug delivery. These data will provide novel ideas for new drug development and the search for new therapeutic mechanisms.},
}

*Alzheimer Disease/therapy/drug therapy
Humans
Genetic Therapy/methods
Amyloid beta-Peptides/metabolism
Animals
Plaque, Amyloid
Neurofibrillary Tangles/pathology
Plant Extracts/therapeutic use

@article {pmid41368288,
year = {2025},
author = {Wang, X and Yang, F and Chen, P and Yang, M and Deng, Y and Zhan, Z},
title = {Mesenchymal Stem Cell-Derived Extracellular Vesicles in Alzheimer's Disease: A Novel Cell-Free Therapeutic Strategy and Diagnostic Biomarker.},
journal = {International journal of nanomedicine},
volume = {20},
number = {},
pages = {14375-14391},
pmid = {41368288},
issn = {1178-2013},
mesh = {*Alzheimer Disease/therapy/diagnosis ; *Extracellular Vesicles/metabolism/transplantation ; Humans ; *Mesenchymal Stem Cells/cytology/metabolism ; Biomarkers/metabolism/analysis ; Animals ; },
abstract = {With the ongoing trend of population aging worldwide, the incidence of Alzheimer's disease (AD) is steadily increasing. In the absence of effective therapeutic options for atypical forms of AD, reducing its prevalence and improving treatment outcomes have become pressing priorities. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have attracted growing attention as a new cell-free therapeutic approach for AD due to their high stability, low immunogenicity, and minimal tumorigenic risk. This review provides a comprehensive overview of the pathological mechanisms underlying AD, highlights the diagnostic potential of MSC-EVs, and elaborates on their therapeutic advantages and mechanisms of action. Furthermore, it addresses the key challenges and considerations associated with the clinical translation of MSC-EVs.},
}

*Alzheimer Disease/therapy/diagnosis
*Extracellular Vesicles/metabolism/transplantation
Humans
*Mesenchymal Stem Cells/cytology/metabolism
Biomarkers/metabolism/analysis
Animals

@article {pmid41367378,
year = {2025},
author = {Toyli, A and Shaik, A and Zhao, C and Chen, QH and Sha, Q and Zhou, W},
title = {The heart-brain axis: unraveling the interconnections between cardiovascular and Alzheimer's diseases.},
journal = {Frontiers in cardiovascular medicine},
volume = {12},
number = {},
pages = {1685461},
pmid = {41367378},
issn = {2297-055X},
abstract = {Cardiovascular disease (CVD) and Alzheimer's disease (AD) are leading causes of death and disability worldwide, and recent research has increasingly illuminated a complex, bidirectional relationship between the two. This review synthesizes epidemiological, mechanistic, imaging, and genetic evidence linking CVD and AD through the heart-brain axis-a network of interrelated physiological and demographic pathways. We detail how cerebral hypoperfusion, inflammation, blood-brain barrier dysfunction, imbalance of the autonomic nervous system, and systemic amyloidosis contribute to shared neurodegenerative and cardiovascular outcomes. Multi-organ imaging studies, including MRI and PET, reveal that dysfunction of the cardiovascular system correlates with brain atrophy, white matter lesions, glymphatic impairment, and accumulation of AD-related proteinopathies. Genetic analyses further support overlapping risk architectures, particularly involving APOE and loci associated with lipid metabolism, vascular integrity, and inflammation. Age and sex are critical modifiers, with midlife CVD exerting the strongest influence on later cognitive decline, and sex-specific physiological responses shaping disease susceptibility. Finally, we explore how modifiable lifestyle factors, pharmacologic interventions, and precision medicine approaches targeting inflammatory and vascular pathways can jointly reduce the burden of both CVD and AD. Multidisciplinary collaboration to understand the interconnected biology of the heart and brain is essential for advancing integrated prevention and treatment strategies in aging populations.},
}